By last October, about three out of every four residents of Manaus, Brazil already had been infected with SARS-CoV-2, the virus that causes COVID-19 [1]. And yet, despite hopes of achieving “herd immunity” in this city of 2.2 million in the Amazon region, the virus came roaring back in late 2020 and early 2021 to cause a second wave of illness and death [2]. How is this possible?

The answer offers a lesson in viral evolution, especially when an infectious virus such as SARS-CoV-2 replicates and spreads through a population largely unchecked. In a recent study in the journal Science, researchers tied the city’s resurgence of SARS-CoV-2 to the emergence and rapid spread of a new SARS-CoV-2 “variant of concern” known as P.1 [3]. This variant carries a unique constellation of mutations that allow it not only to sneak past the human immune system and re-infect people, but also to be about twice as transmissible as earlier variants.

To understand how this is possible, consider that each time the coronavirus SARS-CoV-2 makes copies of itself in an infected person, there’s a chance a mistake will be made. Each mistake can produce a new variant that may go on to make more copies of itself. In most cases, those random errors are of little to no consequence. This is evolution in action.

But sometimes a spelling change can occur that benefits the virus. In the special case of patients with suppressed immune systems, the virus can have ample opportunity to accrue an unusually high number of mutations. Variants carrying beneficial mutations can make more copies of themselves than other variants, allowing them to build their numbers and spread to cause more infection.

At this advanced stage of the COVID-19 pandemic, such rapidly spreading new variants remain cause for serious concern. That includes variants such as B.1.351, which originated in South Africa; B.1.1.7 which emerged in the United Kingdom; and now P.1 from Manaus, Brazil.

In the new study, Nuno Faria and Samir Bhatt, Imperial College London, U.K., and Ester Cerdeira Sabino, Universidade de Sao Paulo, Brazil, and their colleagues sequenced SARS-CoV-2 genomes from 184 patient samples collected in Manaus in November and December 2020. The research was conducted under the auspices of the Brazil-UK Centre for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE), a project focused on viral genomics and epidemiology for public health.

Those genomic data revealed the P.1 variant had acquired 17 new mutations. Ten were in the spike protein, which is the segment of the virus that binds onto human cells and the target of current COVID-19 vaccines. In fact, the new work reveals that three of these spike protein mutations make it easier for the P.1 spike to bind the human ACE2 receptor, which is SARS-CoV-2’s preferred entry point.

The first P.1 variant case was detected by genomic surveillance on December 6, 2020, after which it spread rapidly. Through further evolutionary analysis, the team estimates that P.1 must have emerged, undetected for a brief time, in mid-November 2020.

To understand better how the P.1 variant led to such an explosion of new COVID-19 cases, the researchers developed a mathematical model that integrated the genomic data with mortality data. The model suggests that P.1 may be 1.7 to 2.4 times more transmissible than earlier variants. They also estimate that a person previously infected with a variant other than P.1 will have only 54 percent to 79 percent protection against a subsequent infection with P.1.

The researchers also observed an increase in mortality following the emergence of the P.1 variant. However, it’s not yet clear if that’s an indication P.1 is inherently more deadly than earlier variants. It’s possible the increased mortality is related primarily to the extra stress on the healthcare system in Manaus from treating so many people with COVID-19.

These findings are yet another reminder of the importance of genomic surveillance and international data sharing for detecting and characterizing emerging SARS-CoV-2 variants quickly. It’s worth noting that at about the same time this variant was detected in Brazil, it also was reported in four individuals who had traveled to Brazil from Japan. The P.1 variant continues to spread rapidly across Brazil. It has also been detected in more than 37 countries [4], including the United States, where it now accounts for more than 1 percent of new cases [5].

No doubt you are wondering what this means for vaccines, such as the Pfizer and Moderna mRNA vaccines, that have been used to immunize (at least one dose) over 140 million people in the United States. Here the news is encouraging. Serum from individuals who received the Pfizer vaccine had titers of neutralizing antibodies that were only slightly reduced for P.1 compared to the original SARS-CoV-2 virus [6]. Therefore, the vaccine is predicted to be highly protective. This is another example of a vaccine providing more protection than a natural infection.

The United States has made truly remarkable progress in combating COVID-19, but we must heed this lesson from Manaus: this terrible pandemic isn’t over just yet. While the P.1 variant remains at low levels here for now, the “U.K. variant” B.1.1.7 continues to spread rapidly and now is the most prevalent variant circulating in the U.S., accounting for 44 percent of new cases [6]. Fortunately, the mRNA vaccines also work well against B.1.1.7.

We must continue to do absolutely everything possible, individually and collectively, to prevent these new SARS-CoV-2 variants from slowing or even canceling the progress made over the last year. We need to remain vigilant for a just a while longer, while encouraging our friends, neighbors, and loved ones to get vaccinated.

References:

[1] Three-quarters attack rate of SARS-CoV-2 in the Brazilian Amazon during a largely unmitigated epidemic. Buss, L. F., C. A. Prete, Jr., C. M. M. Abrahim, A. C. Dye, V. H. Nascimento, N. R. Faria and E. C. Sabino et al. (2021). Science 371(6526): 288-292.

[2] Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence. Sabino EC, Buss LF, Carvalho MPS, Prete Jr CCA, Crispim MAE, Fraiji NA, Pereira RHM, Paraga KV, Peixoto PS, Kraemer MUG, Oikawa MJ, Salomon T, Cucunuba ZM, Castro MC, Santos AAAS, Nascimento VH, Pereira HS, Ferguson NM, Pybus OG, Kucharski A, Busch MP, Dye C, Faria NR Lancet. 2021 Feb 6;397(10273):452-455.

[3] Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil. Faria NR, Mellan TA, Whittaker C, Claro IM, Fraiji NA, Carvalho MDPSS, Pybus OG, Flaxman S, Bhatt S, Sabino EC et al. Science. 2021 Apr 14:eabh2644.

[4] GRINCH Global Report Investigating novel coronavirus haplotypes. PANGO Lineages.

[5] COVID Data Tracker. Variant Proportions. Centers for Disease Control and Prevention.

[6] Antibody evasion by the P.1 strain of SARS-CoV-2. Dejnirattisai W, Zhou D, Supasa P, Liu C, Mongkolsapaya J, Ren J, Stuart DI, Screaton GR, et al. Cell. 2021 Mar 30:S0092-8674(21)00428-1.

Links:

COVID-19 Research (NIH)

Brazil-UK Centre for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE)

Nuno Faria (Imperial College, London, U.K.)

Samir Bhatt (Imperial College)

Ester Cerdeira Sabino (Universidade de Sao Paulo, Brazil)

NIH Support: National Institute of Allergy and Infectious Diseases

Caption: SARS-CoV-2 (pink) and its preferred human receptor ACE2 (white) were found in human salivary gland cells (outlined in green). Credit: Paola Perez, Warner Lab, National Institute of Dental and Craniofacial Research, NIH

COVID-19 is primarily considered a respiratory illness that affects the lungs, upper airways, and nasal cavity. But COVID-19 can also affect other parts of the body, including the digestive system, blood vessels, and kidneys. Now, a new study has added something else: the mouth.

The study, published in the journal Nature Medicine, shows that SARS-CoV-2, which is the coronavirus that causes COVID-19, can actively infect cells that line the mouth and salivary glands. The new findings may help explain why COVID-19 can be detected by saliva tests, and why about half of COVID-19 cases include oral symptoms, such as loss of taste, dry mouth, and oral ulcers. These results also suggest that the mouth and its saliva may play an important—and underappreciated—role in spreading SARS-CoV-2 throughout the body and, perhaps, transmitting it from person to person.

The latest work comes from Blake Warner of NIH’s National Institute of Dental and Craniofacial Research; Kevin Byrd, Adams School of Dentistry at the University of North Carolina, Chapel Hill; and their international colleagues. The researchers were curious about whether the mouth played a role in transmitting SARS-CoV-2. They were already aware that transmission is more likely when people speak, cough, and even sing. They also knew from diagnostic testing that the saliva of people with COVID-19 can contain high levels of SARS-CoV-2. But did that virus in the mouth and saliva come from elsewhere? Or, was SARS-CoV-2 infecting and replicating in cells within the mouth as well?

To find out, the research team surveyed oral tissue from healthy people in search of cells that express the ACE2 receptor protein and the TMPRSS2 enzyme protein, both of which SARS-CoV-2 depends upon to enter and infect human cells. They found the proteins to be expressed individually in the primary cells of all types of salivary glands and in tissues lining the oral cavity. Indeed, a small portion of salivary gland and gingival (gum) cells around our teeth, simultaneously expressed both ACE2 and TMPRSS2.

Next, the team detected signs of SARS-CoV-2 in just over half of the salivary gland tissue samples that it examined from people with COVID-19. The samples included salivary gland tissue from one person who had died from COVID-19 and another with acute illness.

The researchers also found evidence that the coronavirus was actively replicating to make more copies of itself. In people with mild or asymptomatic COVID-19, oral cells that shed into the saliva bathing the mouth were found to contain RNA for SARS-CoV-2, as well its proteins that it uses to enter human cells.

The researchers then collected saliva from another group of 35 volunteers, including 27 with mild COVID-19 symptoms and another eight who were asymptomatic. Of the 27 people with symptoms, those with virus in their saliva were more likely to report loss of taste and smell, suggesting that oral infection might contribute to those symptoms of COVID-19, though the primary cause may be infection of the olfactory tissues in the nose.

Another important question is whether SARS-CoV-2, while suspended in saliva, can infect other healthy cells. To get the answer, the researchers exposed saliva from eight people with asymptomatic COVID-19 to healthy cells grown in a lab dish. Saliva from two of the infected volunteers led to infection of the healthy cells. These findings raise the unfortunate possibility that even people with asymptomatic COVID-19 might unknowingly transmit SARS-CoV-2 to other people through their saliva.

Overall, the findings suggest that the mouth plays a greater role in COVID-19 infection and transmission than previously thought. The researchers suggest that virus-laden saliva, when swallowed or inhaled, may spread virus into the throat, lungs, or digestive system. Knowing this raises the hope that a better understanding of how SARS-CoV-2 infects the mouth could help in pointing to new ways to prevent the spread of this devastating virus.

Reference:

[1] SARS-CoV-2 infection of the oral cavity and saliva. Huang N, Pérez P, Kato T, Mikami Y, Chiorini JA, Kleiner DE, Pittaluga S, Hewitt SM, Burbelo PD, Chertow D; NIH COVID-19 Autopsy Consortium; HCA Oral and Craniofacial Biological Network, Frank K, Lee J, Boucher RC, Teichmann SA, Warner BM, Byrd KM, et. al Nat Med. 2021 Mar 25.

Links:

COVID-19 Research (NIH)

Saliva & Salivary Gland Disorders (National Institute of Dental and Craniofacial Research/NIH)

Blake Warner (National Institute of Dental and Craniofacial Research/NIH)

Kevin Byrd (Adams School of Dentistry at University of North Carolina, Chapel Hill)

NIH Support: National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases

Since the genome sequence of SARS-CoV-2, the virus responsible for COVID-19, was first reported in January 2020, thousands of variants have been reported. In the vast majority of cases, these variants, which arise from random genomic changes as SARS-CoV-2 makes copies of itself in an infected person, haven’t raised any alarm among public health officials. But that’s now changed with the emergence of at least three variants carrying mutations that potentially make them even more dangerous.

At the top of this short list is a variant known as B.1.1.7, first detected in the United Kingdom in September 2020. This variant is considerably more contagious than the original virus. It has spread rapidly around the globe and likely accounts already for at least one-third of all cases in the United States [1]. Now comes more troubling news: emerging evidence indicates that infection with this B.1.1.7 variant also comes with an increased risk of severe illness and death [2].

The findings, reported in Nature, come from Nicholas Davies, Karla Diaz-Ordaz, and Ruth Keogh, London School of Hygiene and Tropical Medicine. The London team earlier showed that this new variant is 43 to 90 percent more transmissible than pre-existing variants that had been circulating in England [3]. But in the latest paper, the researchers followed up on conflicting reports about the virulence of B.1.1.7.

They did so with a large British dataset linking more than 2.2 million positive SARS-CoV-2 tests to 17,452 COVID-19 deaths from September 1, 2020, to February 14, 2021. In about half of the cases (accounting for nearly 5,000 deaths), it was possible to discern whether or not the infection had been caused by the B.1.1.7 variant.

Based on this evidence, the researchers calculated the risk of death associated with B.1.1.7 infection. Their estimates suggest that B.1.1.7 infection was associated with 55 percent greater mortality compared to other SARS-CoV-2 variants over this time period.

For a 55- to 69-year-old male, this translates to a 0.9-percent absolute, or personal, risk of death, up from 0.6 percent for the older variants. That means nine in every 1,000 people in this age group who test positive with the B.1.1.7 variant would be expected to die from COVID-19 a month later. For those infected with the original virus, that number would be six.

Adapted from Centers for Disease Control and Prevention

These findings are in keeping with those of another recent study reported in the British Medical Journal [4]. In that case, researchers at the University of Exeter and the University of Bristol found that the B.1.1.7 variant was associated with a 64 percent greater chance of dying compared to earlier variants. That’s based on an analysis of data from more than 100,000 COVID-19 patients in the U.K. from October 1, 2020, to January 28, 2021.

That this variant comes with increased disease severity and mortality is particularly troubling news, given the highly contagious nature of B.1.1.7. In fact, Davies’ team has concluded that the emergence of new SARS-CoV-2 variants now threaten to slow or even cancel out improvements in COVID-19 treatment that have been made over the last year. These variants include not only B1.1.7, but also B.1.351 originating in South Africa and P.1 from Brazil.

The findings are yet another reminder that, while we’re making truly remarkable progress in the fight against COVID-19 with increasing availability of safe and effective vaccines (more than 45 million Americans are now fully immunized), now is not the time to get complacent. This devastating pandemic isn’t over yet.

The best way to continue the fight against all SARS-CoV-2 variants is for each one of us to do absolutely everything we can to stop their spread. This means that taking the opportunity to get vaccinated as soon as it is offered to you, and continuing to practice those public health measures we summarize as the three Ws: Wear a mask, Watch your distance, Wash your hands often.

References:

[1] US COVID-19 Cases Caused by Variants. Centers for Disease Control and Prevention.

[2] Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7. Davies NG, Jarvis CI; CMMID COVID-19 Working Group, Edmunds WJ, Jewell NP, Diaz-Ordaz K, Keogh RH. Nature. 2021 Mar 15.

[3] Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Davies NG, Abbott S, Barnard RC, Jarvis CI, Kucharski AJ, Munday JD, Pearson CAB, Russell TW, Tully DC, Washburne AD, Wenseleers T, Gimma A, Waites W, Wong KLM, van Zandvoort K, Silverman JD; CMMID COVID-19 Working Group; COVID-19 Genomics UK (COG-UK) Consortium, Diaz-Ordaz K, Keogh R, Eggo RM, Funk S, Jit M, Atkins KE, Edmunds WJ.Science. 2021 Mar 3:eabg3055.

[4] Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study. Challen R, Brooks-Pollock E, Read JM, Dyson L, Tsaneva-Atanasova K, Danon L. BMJ. 2021 Mar 9;372:n579.Links:

COVID-19 Research (NIH)Nicholas Davies (London School of Hygiene and Tropical Medicine, U.K.)Ruth Keogh (London School of Hygiene and Tropical Medicine, U.K.)

Credit: Getty Images

It’s become increasingly clear that even healthy people with mild cases of COVID-19 can battle a constellation of symptoms that worsen over time—or which sometimes disappear only to come right back. These symptoms are part of what’s called “Long COVID Syndrome.”

Now, a new study of relatively young, healthy adult healthcare workers in Sweden adds needed information on the frequency of this Long COVID Syndrome. Published in the journal JAMA, the study found that just over 1 in 10 healthcare workers who had what at first seemed to be a relatively mild bout of COVID-19 were still coping with at least one moderate to severe symptom eight months later [1]. Those symptoms—most commonly including loss of smell and taste, fatigue, and breathing problems—also negatively affected the work and/or personal lives of these individuals.

These latest findings come from the COVID-19 Biomarker and Immunity (COMMUNITY) study, led by Charlotte Thålin, Danderyd Hospital and Karolinska Institutet, Stockholm. The study, launched a year ago, enlisted 2,149 hospital employees to learn more about immunity to SARS-CoV-2, the coronavirus that causes COVID-19.

After collecting blood samples from participants, the researchers found that about 20 percent already had antibodies to SARS-CoV-2, evidence of a past infection. Thålin and team continued collecting blood samples every four months from all participants, who also completed questionnaires about their wellbeing.

Intrigued by recent reports in the medical literature that many people hospitalized with COVID-19 can have persistent symptoms for months after their release, the researchers decided to take a closer look in their COMMUNITY cohort. They did so last January during their third round of follow up.

This group included 323 mostly female healthcare workers, median age of 43. The researchers compared symptoms in this group following mild COVID-19 to the 1,072 mostly female healthcare workers in the study (median age 47 years) who hadn’t had COVID-19. They wanted to find out if those with mild COVID-19 coped with more and longer-lasting symptoms of feeling unwell than would be expected in an otherwise relatively healthy group of people. These symptoms included familiar things such as fatigue, muscle pain, trouble sleeping, and problems breathing.

Their findings show that 26 percent of those who had mild COVID-19 reported at least one moderate to severe symptom that lasted more than two months. That’s compared to 9 percent of participants without COVID-19. What’s more, 11 percent of the individuals with mild COVID-19 had at least one debilitating symptom that lasted for at least eight months. In the group without COVID-19, any symptoms of feeling unwell resolved relatively quickly.

The most common symptoms in the COVID-19 group were loss of taste or smell, fatigue, and breathing problems. In this group, there was no apparent increase in other symptoms that have been associated with COVID-19, including “brain fog,” problems with memory or attention, heart palpitations, or muscle and joint pain.

The researchers have noted that the Swedish healthcare workers represent a relatively young and healthy group of working individuals. Yet, many of them continued to suffer from lasting symptoms related to mild COVID-19. It’s a reminder that COVID-19 can and, in fact, is having a devastating impact on the lives and livelihoods of adults who are at low risk for developing severe and life-threatening COVID-19. If we needed one more argument for getting young people vaccinated, this is it.

At NIH, efforts have been underway for some time to identify the causes of Long COVID. In fact, a virtual workshop was held last winter with more than 1,200 participants to discuss what’s known and to fill in key gaps in our knowledge of Long COVID syndrome, which is clinically known as post-acute sequelae of COVID-19 (PASC). Recently, a workshop summary was published [2]. As workshops and studies like this one from Sweden help to define the problem., the hope is to learn one day how to treat or prevent this terrible condition. The NIH is now investing more than $1 billion in seeking those answers.

References:

[1] Symptoms and functional impairment assessed 8 Months after mild COVID-19 among health care workers. Havervall S, Rosell A, Phillipson M, Mangsbo SM, Nilsson P, Hober S, Thålin C. JAMA. 2021 Apr 7.[2] Toward understanding COVID-19 recovery: National Institutes of Health workshop on postacute COVID-19. Lerner A, et al. Ann Intern Med, 2021 March 30.

Links:

COVID-19 Research (NIH)

Charlotte Thålin (Karolinska Institutet, Stockholm, Sweden)

It was my pleasure to be a panelist during a recent virtual forum titled “Building Vaccine Confidence: Best Practices to Combat Misinformation and Vaccine Hesitancy in COVID-19 Vaccines.” The forum took place during the American Association for Cancer Research’s Annual Meeting 2021, which had more than 13,500 registrants. This screenshot shows the panel getting ready for our informative discussion on building confidence in the COVID-19 vaccines. The panelists are (from top l-r): Gilbert S. Omenn (co-moderator), University of Michigan, Ann Arbor; Antoni Ribas (co-moderator), University of California Los Angeles; yours truly Francis Collins; E. John Wherry, University of Pennsylvania, Philadelphia; Grace Cordovano, Enlightening Results, LLC, West Caldwell, NJ; Lisa Richardson, Centers for Disease Control and Prevention, Atlanta; Liz Hamel, Henry J. Kaiser Family Foundation, San Francisco; Lee Greenberger, Leukemia & Lymphoma Society, Rye Brook, NY; and Mary Gullatte, EMORY Healthcare, Atlanta. The forum took place on April 14, 2021.

Not too long after the global coronavirus disease 2019 (COVID-19) pandemic reached the United States, museum curators began collecting material to document the history of this devastating public health crisis and our nation’s response to it. To help tell this story, the Smithsonian Institution’s National Museum of American History recently scored a donation from my friend and colleague Dr. Anthony Fauci, Director of NIH’s National Institute of Allergy and Infectious Diseases.

Widely recognized for serving as a clear voice for science throughout the pandemic, Fauci gave the museum his much-used model of SARS-CoV-2, which is the coronavirus that causes COVID-19. This model, which is based on work conducted by NIH-supported electron microscopists and structural biologists, was 3D printed right here at NIH. By the way, I’m lucky enough to have one too.

Both of these models have “met” an amazing array of people—from presidents to congresspeople to journalists to average citizens—as part of our efforts to help folks understand SARS-CoV-2 and the crucial role of its surface spike proteins. As shown in this brief video, Fauci raised his model one last time and then, ever the public ambassador for science, turned his virtual donation into a memorable teaching moment. I recommend you take a minute or two to watch it.

The donation took place during a virtual ceremony in which the National Museum of American History awarded Fauci its prestigious Great Americans Medal. He received the award for his lifetime contributions to the nation’s ideals and for making a lasting impact on public health via his many philanthropic and humanitarian efforts. Fauci joined an impressive list of luminaries in receiving this honor, including former Secretaries of State Madeleine Albright and General Colin Powell; journalist Tom Brokaw; baseball great Cal Ripken Jr.; tennis star Billie Jean King; and musician Paul Simon. It’s a well-deserved honor for a physician-scientist who’s advised seven presidents on a range of domestic and global health issues, from HIV/AIDS to Ebola to COVID-19.

With Fauci’s model now enshrined as an official piece of U.S. history, the Smithsonian and other museums around the world are stepping up their efforts to gather additional artifacts related to COVID-19 and to chronicle its impacts on the health and economy of our nation. Hopefully, future generations will learn from this history so that humankind is not doomed to repeat it.

It is interesting to note that the National Museum of American History’s collection contains few artifacts from another tragic chapter in our nation’s past: the 1918 Influenza Pandemic. One reason this pandemic went largely undocumented is that, like so many of their fellow citizens, curators chose to overlook its devastating impacts and instead turn toward the future.

An NIH staff member created these paper flowers from the stickers received over the past several months each time he was screened for COVID-19 at the NIH Clinical Center. Credit: Office of NIH History and Stetten Museum

Today, museum staffers across the country and around the world are stepping up to the challenge of documenting COVID-19’s history with great creativity, collecting all variety of masks, test kits, vaccine vials, and even a few ventilators. At the NIH’s main campus in Bethesda, MD, the Office of NIH History and Stetten Museum is busy preparing a small exhibit of scientific and clinical artifacts that could open as early as the summer of 2021. The museum is also collecting oral histories as part of its “Behind the Mask” project. So far, more than 50 interviews have been conducted with NIH staff, including a scientist who’s helping the hard-hit Navajo Nation during the pandemic; a Clinical Center nurse who’s treating patients with COVID-19, and a mental health professional who’s had to change expectations since the outbreak.

The pandemic isn’t over yet. All of us need to do our part by getting vaccinated against COVID-19 and taking other precautions to prevent the virus’s deadly spread. But won’t it great when—hopefully, one day soon—we can relegate this terrible pandemic to the museums and the history books!

Links:

COVID-19 Research (NIH)

Video: National Museum of American History Presents The Great Americans Medal to Anthony S. Fauci (Smithsonian Institution, Washington, D.C.)National Museum of American History (Smithsonian)

The Office of NIH History and Stetten Museum (NIH)

Caption: Image shows macrophages (red), fibroblast cells (green), and other cells (blue). In late COVID-19, macrophages migrate near fibroblasts, which may play a role in fibrosis. Credit: Images courtesy of André Rendeiro

A crucial question for COVID-19 researchers is what causes progression of the initial infection, leading to life-threatening respiratory illness. A good place to look for clues is in the lungs of those COVID-19 patients who’ve tragically lost their lives to acute respiratory distress syndrome (ARDS), in which fluid and cellular infiltrates build up in the lung’s air sacs, called alveoli, keeping them from exchanging oxygen with the bloodstream.

As shown above, a team of NIH-funded researchers has done just that, capturing changes in the lungs over the course of a COVID-19 infection at unprecedented, single-cell resolution. These imaging data add evidence that SARS-CoV-2, the coronavirus that causes COVID-19, primarily infects cells at the surface of the air sacs. Their findings also offer valuable clues for treating the most severe consequences of COVID-19, suggesting that a certain type of scavenging immune cell might be driving the widespread lung inflammation that leads to ARDS.

The findings, published in Nature [1], come from Olivier Elemento and Robert E. Schwartz, Weill Cornell Medicine, New York. They already knew from earlier COVID-19 studies about the body’s own immune response causing the lung inflammation that leads to ARDS. What was missing was an understanding of the precise interplay between immune cells and lung tissue infected with SARS-CoV-2. It also wasn’t clear how the ARDS seen with COVID-19 compared to the ARDS seen in other serious respiratory diseases, including influenza and bacterial pneumonia.

Traditional tissue analysis uses chemical stains or tagged antibodies to label certain proteins and visualize important features in autopsied human tissues. But using these older techniques, it isn’t possible to capture more than a few such proteins at once. To get a more finely detailed view, the researchers used a more advanced technology called imaging mass cytometry [2].

This approach uses a collection of lanthanide metal-tagged antibodies to label simultaneously dozens of molecular markers on cells within tissues. Next, a special laser scans the labeled tissue sections, which vaporizes the heavy metal tags. As the metals are vaporized, their distinct signatures are detected in a mass spectrometer along with their spatial position relative to the laser. The technique makes it possible to map precisely where a diversity of distinct cell types is located in a tissue sample with respect to one another.

In the new study, the researchers applied the method to 19 lung tissue samples from patients who had died of severe COVID-19, acute bacterial pneumonia, or bacterial or influenza-related ARDS. They included 36 markers to differentiate various types of lung and immune cells as well as the SARS-CoV-2 spike protein and molecular signs of immune activation, inflammation, and cell death. For comparison, they also mapped four lung tissue samples from people who had died without lung disease.

Altogether, they captured more than 200 lung tissue maps, representing more than 660,000 cells across all the tissues sampled. Those images showed in all cases that respiratory infection led to a thickening of the walls surrounding alveoli as immune cells entered. They also showed an increase in cell death in infected compared to healthy lungs.

Their maps suggest that what happens in the lungs of COVID-19 patients who die with ARDS isn’t entirely unique. It’s similar to what happens in the lungs of those with other life-threatening respiratory infections who also die with ARDS.

They did, however, reveal a potentially prominent role in COVID-19 for white blood cells called macrophages. The results showed that macrophages are much more abundant in the lungs of severe COVID-19 patients compared to other lung infections.

In late COVID-19, macrophages also increase in the walls of alveoli, where they interact with lung cells known as fibroblasts. This suggests these interactions may play a role in the buildup of damaging fibrous tissue, or scarring, in the alveoli that tends to be seen in severe COVID-19 respiratory infections.

While the virus initiates this life-threatening damage, its progression may not depend on the persistence of the virus, but on an overreaction of the immune system. This may explain why immunomodulatory treatments like dexamethasone can provide benefit to the sickest patients with COVID-19. To learn even more, the researchers are making their data and maps available as a resource for scientists around the world who are busily working to understand this devastating illness and help put an end to the terrible toll caused by this pandemic.

References:

[1] The spatial landscape of lung pathology during COVID-19 progression. Rendeiro AF, Ravichandran H, Bram Y, Chandar V, Kim J, Meydan C, Park J, Foox J, Hether T, Warren S, Kim Y, Reeves J, Salvatore S, Mason CE, Swanson EC, Borczuk AC, Elemento O, Schwartz RE. Nature. 2021 Mar 29.

[2] Mass cytometry imaging for the study of human diseases-applications and data analysis strategies. Baharlou H, Canete NP, Cunningham AL, Harman AN, Patrick E. Front Immunol. 2019 Nov 14;10:2657.

Links:

COVID-19 Research (NIH)

Elemento Lab (Weill Cornell Medicine, New York)

Schwartz Lab (Weill Cornell Medicine)

NIH Support: National Center for Advancing Translational Sciences; National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute

On April 8, I sent a coronavirus update to NIH staff titled “Gratitude for All You Do.” The update included a link to this video, and these words:No one will deny that this last year has been a struggle for all of us. But now, because of your contributions, we have real reason for hope. As I’ve been known to do, I’ve turned to music to share my gratitude for all you do. This song is a different take on George Harrison’s “Here Comes the Sun” made famous by the Beatles. As with all things, I had the help of many talented people in the creation of this music video: Carrie Wolinetz, who “COVIDized” the song lyrics; my wife Diane, who I heavily rely on for her videography skills (and most other things in life); Wole Akinso, who produced and mixed the video so that I could play both guitar and piano; and my cat Zoe, who in typical cat fashion, made a cameo appearance. I never thought I’d sing a song that has the words “herd immunity” in it, but here we are. I hope this version of the song puts a smile on your faces.I wish the same for all who watch this video. It’s been a long, dark COVID winter.

Every spring, I and my colleague Dr. Nora Volkow, Director of NIH’s National Institute on Drug Abuse (NIDA), join with leaders across the country in the Rx Drug Abuse and Heroin Summit. Our role is to discuss NIH’s continued progress in tackling our nation’s opioid crisis. Because of the continued threat of COVID-19 pandemic, we joined in virtually for the second year in a row.

While the demands of the pandemic have been challenging for everyone, biomedical researchers have remained hard at work to address the opioid crisis. Among the many ways that NIH is supporting these efforts is through its Helping to End Addiction Long-Term (HEAL) Initiative, which is directing more than $1.5 billion to researchers and communities across the country.

Here’s a condensed transcript of our April 6th video dialogue, which focused on the impact of the COVID-19 pandemic on people struggling with substance use disorders and those who are trying to help them.

Collins: What have we learned so far through HEAL? Well, one thing HEAL is doing is tackling the need for pain treatments that help people avoid the risks of opioids. This research has uncovered new targets and therapeutics for different types of pain, including neuropathic, post-surgical, osteoarthritic, and chemotherapy induced. We’re testing implanted devices, such as electrodes and non-invasive nerve stimulation; and looking at complementary and integrative approaches, such as phone-based physical therapy for low back pain.

Through HEAL, we’ve launched a first-in-human test of a vaccine to protect against the harmful effects of opioids, including relapse and overdose. We’re also testing a tool that provides pharmacists with a validated opioid use disorder risk measure. The goal is to identify better who’s at high risk for opioid addiction and to determine what kind of early intervention could be put in place.

Despite COVID, many clinical studies are now recruiting participants. This includes family-based prevention programs, culturally tailored interventions for hard-hit American Indian populations, and interventions that address social inequities, such as lack of housing.

We are also making progress on the truly heart-breaking problem of babies born dependent on opioids. HEAL has launched a study to test the effectiveness of a new approach to care that measures the severity of a baby’s withdrawal, based on their ability to eat, sleep, and be consoled. This approach helps provide appropriate treatment for these infants, without the use of medication when possible. We’re also developing novel technologies to help treat neonatal opioid withdrawal syndrome, including a gently vibrating hospital bassinet pad that’s received breakthrough device designation from the FDA.

2020 was an extraordinary year that was tragic in so many ways, including lives lost and economic disasters that have fallen upon families. The resilience and ingenuity of the scientific community has been impressive. Quick pivoting has resulted in some gains through research, maybe you could even call them silver linings in the midst of this terrible storm.

Nora, what’s been at the forefront of your mind as we’ve watched things unfold?

Volkow: When we did this one year ago, we didn’t know what to expect. Obviously, we were concerned that the stressors associated with a pandemic, with unknowns, are factors that have been recognized for many years to increase drug use. Unfortunately, what we’ve seen is an increase in drug use of all types across the country.

We have seen an exacerbation of the opioid epidemic, as evidenced by the number of people who have died. Already, in the 12 months ending in July 2020, there was a 24 percent increase in mortality from overdoses. Within those numbers, there was close to a 50 percent increase in mortality associated with fentanyl. We’re also seeing an increase, not just in deaths from fentanyl and other synthetic opioids, but in deaths from stimulant drugs, like cocaine and methamphetamine. And the largest increases have been very much driven by drug combinations.

So, we have the perfect storm. We have people stressed to their limits by decreases in the economy, the loss of jobs, the death of loved ones. On the other hand, we see dealers taking the opportunity to bring in drugs such as synthetic opioids and synthetic stimulants and distribute them to a much wider extent than previously seen.

Collins: On top of that, people are at risk of getting sick from COVID-19. What have we learned about the risks of coronavirus illness for people who use drugs?

Volkow: It is a double whammy. When you look at the electronic health records about the outcomes of people diagnosed with substance use disorders, you consistently see an increased risk for getting infected with COVID-19. And if you look at those who get infected, you observe a significantly increased risk of dying from COVID.

What’s driving this vulnerability? One factor is the pharmacological effects of these drugs. Basically, all of the drugs of abuse that result in addiction, notably opioids, damage the cardiopulmonary system. Some also damage the immune system. And we know that individuals who have any disruption of cardiovascular health, pulmonary health, immune function, or metabolism are at higher risk of getting infected with COVID-19 and having adverse outcomes.

But there’s another factor that’s as important—one that’s very tractable. It is the way in which our society has dealt with substance use disorders: not actually treating them as a disease that requires intervention and support for recovery. The stigmatization of individuals with addiction, the lack of access to treatment, the social isolation, have all created havoc by making these individuals so much more vulnerable to get infected with COVID-19.

They will not go to a doctor. They don’t want to be stigmatized. They need to go out into the streets to get access to the drugs. Many times, they don’t have a choice of what drugs to take because they cannot afford anything except what’s offered to them. So, many, especially those who are minorities, end up homeless or in jails or prison. Even before COVID, we knew that prisons and jails are places where infections can transmit extraordinary rapidly. You could see this was going to result in very negative outcomes for this group of individuals.

Collins: Nora, tell us more about the trends contributing to the current crisis. Maybe three or four years ago, what was going straight up was opioid use, especially heroin. Then, fentanyl started coming up very fast and that has continued. Now, we are seeing more stimulants and mixing of different types of drugs. What is the basis for this?

Volkow: At the beginning of the opiate pandemic, mortality was mainly associated with white Americans, many in rural or semi-suburban areas of the Appalachian states and in New Mexico and Arizona. That has shifted. The highest increase in mortality from opioids, predominantly driven by fentanyl, is now among Black Americans. They’ve had very, very high rates of mortality during the COVID pandemic. And when you look at mortality from methamphetamine, it’s chilling to realize that the risk of dying from methamphetamine overdose is 12-fold higher among American Indians and Alaskan Natives than other groups. This should make us pause to think about what’s driving these terrible racial disparities.

As for drug combinations, many deaths from methamphetamine or cocaine—an estimated 50 percent—are linked to these stimulant drugs being combined with fentanyl or heroin. Dealers are lacing these non-opioid drugs with cheaper, yet potent, opioids to make a larger profit. Someone who’s addicted to a stimulant drug like cocaine or methamphetamine is not tolerant to opioids, which means they are going to be at high risk of overdose if they get a stimulant drug that’s laced with an opioid like fentanyl. That’s been contributing to the sharp rise in mortality from non-opioid drugs.

Collins: I’m glad you raised the issue of health disparities. 2020 will go down as a year in which our nation had to focus on three public health crises at once. The first is the crisis of opioid use disorder and rising mortality from use of other drugs. The second is COVID-19. And the third is the realization, although the problem has been there all along, that health disparities continue to shorten the lives of far too many people.

The latter crisis has little to do with biology, but everything to do with the way in which our society still is afflicted by structural racism. We at NIH are looking at this circumstance, realizing that our own health disparities research agenda needs to be rethought. We have not fully incorporated all the factors that play out in health inequities and racial inequities in our country.

You were also talking about how stimulants have become more widespread. What about treatments for people with stimulant use disorders?

Volkow: For opioid addiction, we’re lucky because we have very effective medications: methadone, buprenorphine, naltrexone. On top of that, we have naloxone, Narcan, that if administered on time, can save the life of a person who has overdosed.

We don’t have any FDA-approved medication for methamphetamine addiction, and we don’t have any overdose reversal for methamphetamine. At the beginning of this year, we funded a large clinical trial aimed at investigating the benefits of the combination of two medications that were already approved as anti-depressants and for the treatment of smoking cessation and alcoholism. It found this combination significantly inhibits the urge to take drugs and therefore helps people stay away from use of methamphetamine. Now, we want to replicate these findings, and to tie that replication study in with guidelines from the FDA on what is needed to approve our new indication for these medications. Why? Because then insurance can cover it, and that will increase the likelihood that people will get treated.

Another exciting possibility is a monoclonal antibody against methamphetamine that’s in Phase 2 clinical trials. If someone comes into the emergency room with an overdose of a combination of opioid and methamphetamine, naloxone often will not work. But this monoclonal antibody with naloxone may offer a greater likelihood of success.Another thing that’s promising is that investigators have been able to modify monoclonal antibodies so they stay in the bloodstream for a longer time. That means we may someday be able to use this passive immunization approach as a treatment for methamphetamine addiction.

Collins: That’s good to hear. Speaking of progress, is there any you want to point to within HEAL?

Volkow: There’s a lot of excitement surrounding medication development. We’re interested in developing antidotes that will be more effective in reversing overdose deaths from fentanyl. We’re also interested in providing longer lasting medications for treatment of opioid use disorders, which would improve the likelihood of patients being protected from overdoses.

The Justice Community Opioid Innovation Network (JCOIN) is another HEAL landmark project. It involves a network of researchers that is working with judges and with the workers in jail and prison systems responsible for taking care of individuals with substance use disorders. Through this network, we’ve been able to start to harmonize practices. One thing that’s been transformative in the jail and prison system has been the embracing of telehealth. In the past, telehealth was not much of a reality in jails and prisons because of the fear of it could lead to communications that could perhaps be considered dangerous. That’s changed due to COVID-19. Now, telehealth is providing access to treatment for individuals in jail and prison, many of them with substance use disorders.

Also, because of COVID, many nonviolent individuals in jails and prisons were released. This gives us an opportunity to evaluate how best to help such individuals achieve recovery from substance use disorders. Hopefully we can generate data to show that there are much more effective strategies than incarceration for dealing with substance use disorders.

The HEALing Communities Study, involves Massachusetts, New York, Ohio, and Kentucky—four of the states with the highest rates of mortality from overdoses from the inception of the opioid epidemic. By implementing a battery of interventions for which there is evidence of benefit, this ambitious study set out to decrease overdose mortality by 40 percent in two years. Then, came COVID and turned everything upside down. Still, because we consolidated interactions between agencies, we’ve been able to apply support systems more efficiently in those communities in ways that have been very, very reinforcing. Obviously, there’ve been delays in implementation of interventions that require in-person interactions or that involve hospital emergency departments, which have been saturated with COVID patients.

We’ve learned a lot in the process. I may be too optimistic, but I do believe that we can stay on goal.

Collins: Now, I’d like to transition to a few questions from people who subscribe to the HEAL website. Announced at this meeting three years ago, the HEAL Initiative involves research participants and patients and stakeholders—especially people who have lived experience with pain, addiction, or both.

Let’s get to the first question: “What is NIH doing through HEAL to address the stigma that prevents people who need opioid medications for treatment from getting them?”

Volkow: A crucial question. As we look at the issue of stigma, we need to recognize that there are structural issues in how our society is prioritizing the importance of substance use disorders and the investments devoted to them. And we need to recognize that substance use disorder doesn’t exist in isolation; it is frequently comorbid with mental illness.

We need to listen. Some of the issues that we believe are most problematic are not. We need to empower these communities to speak up and help them do so. This is probably one of the most important things that we can do in terms of addressing stigma for addiction.

Collins: Absolutely. The HEAL Initiative has a number of projects that are focusing on stigma and coming up with tools to help reduce this. And here’s our second question: “In small communities, how can we provide more access to medications for opioid use disorder?”

Volkow: One project funded through HEAL was to evaluate the effectiveness of community pharmacies for delivering buprenorphine to individuals with opioid use disorder. The results show that patients receiving buprenorphine through community pharmacies in rural areas had as good outcomes as patients being treated by specialized clinicians on site.Another change that’s made things easier is that in March 2020, the DEA relaxed its rules on how a physician can prescribe buprenorphine. In the past, you needed to go physically to see a doctor. Now, the DEA allows a patient to be initiated on buprenorphine through telehealth, and that’s opened the possibility of greater access to treatment in rural communities.

My perspective is let’s look at innovative ways of solving problems. Because the technology is changing in so many ways and so rapidly, let’s take advantage of it.

Collins: Totally with you on that. If there’s a silver lining to COVID-19, it’s that we’ve been forced to take stock of the ways we’ve been doing things. We will learn from this pandemic and change the way we approach so many things in health and medicine as a result. Certainly, opioid use disorder ought to be very high on that list. Let’s move on to another question: “What is the HEAL initiative doing to promote prevention of opioid use?”

Volkow: This is where the HEAL initiative is aiming to provide alternative treatments for the management of pain that reduce the risk of addiction.

Then there’s the issue of prevention in people who start to take opioids because they either want to get high or escape. With the COVID pandemic, we’ve seen increases in anxiety and in depression. Those are factors that can put a teenager or young adult on a trajectory for higher risk of substance use disorders.

So, what is HEAL doing? There is prevention research specifically targeted, for example, at the transition from adolescence to young adulthood. That is the period of greatest vulnerability of uptake of opioids, or drugs of misuse. We’re also targeting minority groups that may be at very, very high risk. We want to be able to understand the factors that make them more vulnerable to tailor prevention interventions more effectively.

Collins: Today, we’ve shared some of the issues that NIH is wrestling with in its efforts to address the crisis of opioid misuse and overdose, as well as other drugs that are now very much part of the challenge. To learn more, go to the HEAL website. You can also send us your thoughts through the HEAL Idea Exchange.

These developments give me hope in the wake of a very difficult year. Clearly, we still have the capacity to work together, we are resilient, and we are determined to put an end to our nation’s opioid crisis.

Volkow: Francis, I want to thank you for your incredible leadership and your support. I hope the COVID pandemic will bring forth a more equitable system, in which all people are given the chance for resilience that maximizes their life, happiness, and productivity. I think science is an extraordinary tool to help us do that.

Links:

Video: The 2021 Rx Drug Abuse & Heroin Summit: Francis Collins with Nora Volkow (NIH)

COVID-19 Research (NIH)

Helping to End Addiction Long-term (HEAL) Initiative (NIH)

HEAL Idea Exchange (NIH)

National Institute on Drug Abuse (NIH)

Rx Drug Abuse & Heroin Summit, A 2021 Virtual Experience

Credit: nito/Shutterstock

Thankfully COVID-19 testing is now more widely available than it was earlier in the pandemic. But getting tested often still involves going to a doctor’s office or community testing site and waiting as long as a couple of days for the results. Testing would be so much easier if people could do it themselves at home. If the result came up positive, a person could immediately self-isolate, helping to stop the coronavirus that causes COVID-19, SARS-CoV-2, from spreading any further in their communities.

That’s why I’m happy to report that the Centers for Disease Control and Prevention (CDC), in close collaboration with state and local public health departments and with NIH, has begun an innovative community health initiative called “Say Yes! COVID Test.” The initiative, the first large-scale evaluation of community-wide, self-administered COVID-19 testing, was launched last week in Pitt County, NC, and will start soon in Chattanooga/Hamilton County, TN.

The initiative will provide as many as 160,000 residents in these two locales with free access to rapid COVID-19 home tests, supplied through NIH’s Rapid Acceleration of Diagnostics (RADx) initiative. Participants can administer these easy-to-use tests themselves up to three times a week for one month. The goal is to assess the benefits of self-administered COVID-19 testing and help guide other communities in implementing similar future programs to slow the spread of COVID-19.

The counties in North Carolina and Tennessee were selected based on several criteria. These included local infection rates; public availability of accurate COVID-19 tracking data, such as that gathered by wastewater surveillance; the presence of local infrastructure needed to support the project; and existing community relationships through RADx’s Underserved Populations (RADx-UP) program. Taken together, these criteria also help to ensure that vulnerable and underserved populations will benefit from the initiative.

The test is called the QuickVue At-Home COVID-19 Test. Developed with RADx support by San Diego-based diagnostic company Quidel, this test is easily performed with a nasal swab and offers results in just 10 minutes. Last week, the test was among several authorized by the Food and Drug Administration (FDA) for over-the-counter use to screen for COVID-19 at home.

Participants can order their QuickVue test kits online for home delivery or local pick up. A free online tool, which was developed with NIH support by CareEvolution, LLC, Ann Arbor, MI, will also be available to provide testing instructions, help in understanding test results, and text message reminders about testing. This innovative tool is also available as a smartphone app.

A recent study, supported by the RADx initiative, found that rapid antigen testing for COVID-19, when conducted at least three times per week, achieves a viral detection level on par with the gold standard of PCR-based COVID-19 testing processed in a lab [1]. That’s especially significant considering the other advantages of a low-cost, self-administered rapid test, including confidential results at home in minutes.

The Say Yes! COVID Test initiative is an important next step in informing the best testing strategies in communities all over the country to end this and future pandemics. The initiative will also help to determine how readily people accept such testing when it’s made available to them. If the foundational data looks promising, the hope is that rapid at-home tests will help to encourage people to protect themselves and others by following the three W’s (Wear a mask. Wash your hands. Watch your distance), getting vaccinated, and saying “Yes” to the COVID-19 test.

Reference:

[1] Longitudinal assessment of diagnostic test performance over the course of acute SARS-CoV-2 infection. Smith RL, Gibson LL, Martinez PP, Heetderks WJ, McManus DD, Brooke CB, et al. medRxiv, 2021 March 20.

Links:

CDC and NIH bring COVID-19 self-testing to residents in two locales, NIH News Release, March 31, 2021

Rapid Acceleration of Diagnostics (RADx) (NIH)

COVID-19 Testing (CDC)

Quidel Corporation (San Diego, CA)

Coronavirus (COVID-19) Update: FDA Continues to Advance Over-the Counter and Other Screening Test Development, FDA News Release, March 31, 2021

NIH Support: National Heart, Lung, and Blood Institute; National Institute of Biomedical Imaging and Bioengineering