spike protein
What A Year It Was for Science Advances!
Posted on by Dr. Francis Collins
At the close of every year, editors and writers at the journal Science review the progress that’s been made in all fields of science—from anthropology to zoology—to select the biggest advance of the past 12 months. In most cases, this Breakthrough of the Year is as tough to predict as the Oscar for Best Picture. Not in 2020. In a year filled with a multitude of challenges posed by the emergence of the deadly coronavirus disease 2019 (COVID-2019), the breakthrough was the development of the first vaccines to protect against this pandemic that’s already claimed the lives of more than 360,000 Americans.
In keeping with its annual tradition, Science also selected nine runner-up breakthroughs. This impressive list includes at least three areas that involved efforts supported by NIH: therapeutic applications of gene editing, basic research understanding HIV, and scientists speaking up for diversity. Here’s a quick rundown of all the pioneering advances in biomedical research, both NIH and non-NIH funded:
Shots of Hope. A lot of things happened in 2020 that were unprecedented. At the top of the list was the rapid development of COVID-19 vaccines. Public and private researchers accomplished in 10 months what normally takes about 8 years to produce two vaccines for public use, with more on the way in 2021. In my more than 25 years at NIH, I’ve never encountered such a willingness among researchers to set aside their other concerns and gather around the same table to get the job done fast, safely, and efficiently for the world.
It’s also pretty amazing that the first two conditionally approved vaccines from Pfizer and Moderna were found to be more than 90 percent effective at protecting people from infection with SARS-CoV-2, the coronavirus that causes COVID-19. Both are innovative messenger RNA (mRNA) vaccines, a new approach to vaccination.
For this type of vaccine, the centerpiece is a small, non-infectious snippet of mRNA that encodes the instructions to make the spike protein that crowns the outer surface of SARS-CoV-2. When the mRNA is injected into a shoulder muscle, cells there will follow the encoded instructions and temporarily make copies of this signature viral protein. As the immune system detects these copies, it spurs the production of antibodies and helps the body remember how to fend off SARS-CoV-2 should the real thing be encountered.
It also can’t be understated that both mRNA vaccines—one developed by Pfizer and the other by Moderna in conjunction with NIH’s National Institute of Allergy and Infectious Diseases—were rigorously evaluated in clinical trials. Detailed data were posted online and discussed in all-day meetings of an FDA Advisory Committee, open to the public. In fact, given the high stakes, the level of review probably was more scientifically rigorous than ever.
First CRISPR Cures: One of the most promising areas of research now underway involves gene editing. These tools, still relatively new, hold the potential to fix gene misspellings—and potentially cure—a wide range of genetic diseases that were once to be out of reach. Much of the research focus has centered on CRISPR/Cas9. This highly precise gene-editing system relies on guide RNA molecules to direct a scissor-like Cas9 enzyme to just the right spot in the genome to cut out or correct a disease-causing misspelling.
In late 2020, a team of researchers in the United States and Europe succeeded for the first time in using CRISPR to treat 10 people with sickle cell disease and transfusion-dependent beta thalassemia. As published in the New England Journal of Medicine, several months after this non-heritable treatment, all patients no longer needed frequent blood transfusions and are living pain free [1].
The researchers tested a one-time treatment in which they removed bone marrow from each patient, modified the blood-forming hematopoietic stem cells outside the body using CRISPR, and then reinfused them into the body. To prepare for receiving the corrected cells, patients were given toxic bone marrow ablation therapy, in order to make room for the corrected cells. The result: the modified stem cells were reprogrammed to switch back to making ample amounts of a healthy form of hemoglobin that their bodies produced in the womb. While the treatment is still risky, complex, and prohibitively expensive, this work is an impressive start for more breakthroughs to come using gene editing technologies. NIH, including its Somatic Cell Genome Editing program, continues to push the technology to accelerate progress and make gene editing cures for many disorders simpler and less toxic.
Scientists Speak Up for Diversity: The year 2020 will be remembered not only for COVID-19, but also for the very public and inescapable evidence of the persistence of racial discrimination in the United States. Triggered by the killing of George Floyd and other similar events, Americans were forced to come to grips with the fact that our society does not provide equal opportunity and justice for all. And that applies to the scientific community as well.
Science thrives in safe, diverse, and inclusive research environments. It suffers when racism and bigotry find a home to stifle diversity—and community for all—in the sciences. For the nation’s leading science institutions, there is a place and a calling to encourage diversity in the scientific workplace and provide the resources to let it flourish to everyone’s benefit.
For those of us at NIH, last year’s peaceful protests and hashtags were noticed and taken to heart. That’s one of the many reasons why we will continue to strengthen our commitment to building a culturally diverse, inclusive workplace. For example, we have established the NIH Equity Committee. It allows for the systematic tracking and evaluation of diversity and inclusion metrics for the intramural research program for each NIH institute and center. There is also the recently founded Distinguished Scholars Program, which aims to increase the diversity of tenure track investigators at NIH. Recently, NIH also announced that it will provide support to institutions to recruit diverse groups or “cohorts” of early-stage research faculty and prepare them to thrive as NIH-funded researchers.
AI Disentangles Protein Folding: Proteins, which are the workhorses of the cell, are made up of long, interconnected strings of amino acids that fold into a wide variety of 3D shapes. Understanding the precise shape of a protein facilitates efforts to figure out its function, its potential role in a disease, and even how to target it with therapies. To gain such understanding, researchers often try to predict a protein’s precise 3D chemical structure using basic principles of physics—including quantum mechanics. But while nature does this in real time zillions of times a day, computational approaches have not been able to do this—until now.
Of the roughly 170,000 proteins mapped so far, most have had their structures deciphered using powerful imaging techniques such as x-ray crystallography and cryo–electron microscopy (cryo-EM). But researchers estimate that there are at least 200 million proteins in nature, and, as amazing as these imaging techniques are, they are laborious, and it can take many months or years to solve 3D structure of a single protein. So, a breakthrough certainly was needed!
In 2020, researchers with the company Deep Mind, London, developed an artificial intelligence (AI) program that rapidly predicts most protein structures as accurately as x-ray crystallography and cryo-EM can map them [2]. The AI program, called AlphaFold, predicts a protein’s structure by computationally modeling the amino acid interactions that govern its 3D shape.
Getting there wasn’t easy. While a complete de novo calculation of protein structure still seemed out of reach, investigators reasoned that they could kick start the modeling if known structures were provided as a training set to the AI program. Utilizing a computer network built around 128 machine learning processors, the AlphaFold system was created by first focusing on the 170,000 proteins with known structures in a reiterative process called deep learning. The process, which is inspired by the way neural networks in the human brain process information, enables computers to look for patterns in large collections of data. In this case, AlphaFold learned to predict the underlying physical structure of a protein within a matter of days. This breakthrough has the potential to accelerate the fields of structural biology and protein research, fueling progress throughout the sciences.
How Elite Controllers Keep HIV at Bay: The term “elite controller” might make some people think of video game whizzes. But here, it refers to the less than 1 percent of people living with human immunodeficiency virus (HIV) who’ve somehow stayed healthy for years without taking antiretroviral drugs. In 2020, a team of NIH-supported researchers figured out why this is so.
In a study of 64 elite controllers, published in the journal Nature, the team discovered a link between their good health and where the virus has inserted itself in their genomes [3]. When a cell transcribes a gene where HIV has settled, this so-called “provirus,” can produce more virus to infect other cells. But if it settles in a part of a chromosome that rarely gets transcribed, sometimes called a gene desert, the provirus is stuck with no way to replicate. Although this discovery won’t cure HIV/AIDS, it points to a new direction for developing better treatment strategies.
In closing, 2020 presented more than its share of personal and social challenges. Among those challenges was a flood of misinformation about COVID-19 that confused and divided many communities and even families. That’s why the editors and writers at Science singled out “a second pandemic of misinformation” as its Breakdown of the Year. This divisiveness should concern all of us greatly, as COVID-19 cases continue to soar around the country and our healthcare gets stretched to the breaking point. I hope and pray that we will all find a way to come together, both in science and in society, as we move forward in 2021.
References:
[1] CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. Frangoul H et al. N Engl J Med. 2020 Dec 5.
[2] ‘The game has changed.’ AI triumphs at protein folding. Service RF. Science. 04 Dec 2020.
[3] Distinct viral reservoirs in individuals with spontaneous control of HIV-1. Jiang C et al. Nature. 2020 Sep;585(7824):261-267.
Links:
COVID-19 Research (NIH)
2020 Science Breakthrough of the Year (American Association for the Advancement of Science, Washington, D.C)
Celebrating the Gift of COVID-19 Vaccines
Posted on by Dr. Francis Collins
The winter holidays are traditionally a time of gift-giving. As fatiguing as 2020 and the COVID-19 pandemic have been, science has stepped up this year to provide humankind with a pair of truly hopeful gifts: the first two COVID-19 vaccines.
Two weeks ago, the U.S. Food and Drug Administration (FDA) granted emergency use authorization (EUA) to a COVID-19 vaccine from Pfizer/BioNTech, enabling distribution to begin to certain high-risk groups just three days later. More recently, the FDA granted an EUA to a COVID-19 vaccine from the biotechnology company Moderna, Cambridge, MA. This messenger RNA (mRNA) vaccine, which is part of a new approach to vaccination, was co-developed by NIH’s National Institute of Allergy and Infectious Diseases (NIAID). The EUA is based on data showing the vaccine is safe and 94.5 percent effective at protecting people from infection with SARS-CoV-2, the coronavirus that causes COVID-19.
Those data on the Moderna vaccine come from a clinical trial of 30,000 individuals, who generously participated to help others. We can’t thank those trial participants enough for this gift. The distribution of millions of Moderna vaccine doses is expected to begin this week.
It’s hard to put into words just how remarkable these accomplishments are in the history of science. A vaccine development process that used to take many years, often decades, has been condensed to about 11 months. Just last January, researchers started out with a previously unknown virus and we now have not just one, but two, vaccines that will be administered to millions of Americans before year’s end. And the accomplishments don’t end there—several other types of COVID-19 vaccines are also on the way.
It’s important to recognize that this couldn’t have happened without the efforts of many scientists working tirelessly behind the scenes for many years prior to the pandemic. Among those who deserve tremendous credit are Kizzmekia Corbett, Barney Graham, John Mascola, and other members of the amazing team at the Dale and Betty Bumpers Vaccine Research Center at NIH’s National Institute of Allergy and Infectious Diseases (NIAID).
When word of SARS-CoV-2 emerged, Corbett, Graham, and other NIAID researchers had already been studying other coronaviruses for years, including those responsible for earlier outbreaks of respiratory disease. So, when word came that this was a new coronavirus outbreak, they were ready to take action. It helped that they had paid special attention to the spike proteins on the surface of coronaviruses, which have turned out to be the main focus the COVID-19 vaccines now under development.
The two vaccines currently authorized for administration in the United States work in a unique way. Their centerpiece is a small, non-infectious snippet of mRNA. Our cells constantly produce thousands of mRNAs, which provide the instructions needed to make proteins. When someone receives an mRNA vaccine for COVID-19, it tells the person’s own cells to make the SARS-CoV-2 spike protein. The person’s immune system then recognizes the viral spike protein as foreign and produces antibodies to eliminate it.
This vaccine-spurred encounter trains the human immune system to remember the spike protein. So, if an actual SARS-CoV-2 virus tries to infect a vaccinated person weeks or months later, his or her immune system will be ready to fend it off. To produce the most vigorous and durable immunity against the virus, people will need to get two shots of mRNA vaccine, which are spaced several weeks to a month apart, depending on the vaccine.
Some have raised concerns on social media that mRNA vaccines might alter the DNA genome of someone being vaccinated. But that’s not possible, since this mRNA doesn’t enter the nucleus of the cell where DNA is located. Instead, the vaccine mRNAs stay in the outer part of the cell (the cytoplasm). What’s more, after being transcribed into protein just one time, the mRNA quickly degrades. Others have expressed concerns about whether the vaccine could cause COVID-19. That is not a risk because there’s no whole virus involved, just the coding instructions for the non-infectious spike protein.
An important advantage of mRNA is that it’s easy for researchers to synthesize once they know the nucleic acid sequence of a target viral protein. So, the gift of mRNA vaccines is one that will surely keep on giving. This new technology can now be used to speed the development of future vaccines. After the emergence of the disease-causing SARS, MERS, and now SARS-CoV-2 viruses, it would not be surprising if there are other coronavirus health threats in our future. Corbett and her colleagues are hoping to design a universal vaccine that can battle all of them. In addition, mRNA vaccines may prove effective for fighting future pandemics caused by other infectious agents and for preventing many other conditions, such as cancer and HIV.
Though vaccines are unquestionably our best hope for getting past the COVID-19 pandemic, public surveys indicate that some people are uneasy about accepting this disease-preventing gift. Some have even indicated they will refuse to take the vaccine. Healthy skepticism is a good thing, but decisions like this ought to be based on weighing the evidence of benefit versus risk. The results of the Pfizer and Moderna trials, all released for complete public scrutiny, indicate the potential benefits are high and the risks, low. Despite the impressive speed at which the new COVID-19 vaccines were developed, they have undergone and continue to undergo a rigorous process to generate all the data needed by the FDA to determine their long-term safety and effectiveness.
Unfortunately, the gift of COVID-19 vaccines comes too late for the more than 313,000 Americans who have died from complications of COVID-19, and many others who’ve had their lives disrupted and may have to contend with long-term health consequences related to COVID-19. The vaccines did arrive in record time, but all of us wish they could somehow have arrived even sooner to avert such widespread suffering and heartbreak.
It will be many months before all Americans who are willing to get a vaccine can be immunized. We need 75-80 percent of Americans to receive vaccines in order to attain the so-called “herd immunity” needed to drive SARS-CoV-2 away and allow us all to get back to a semblance of normal life.
Meanwhile, we all have a responsibility to do everything possible to block the ongoing transmission of this dangerous virus. Each of us needs to follow the three W’s: Wear a mask, Watch your distance, Wash your hands often.
When your chance for immunization comes, please roll up your sleeve and accept the potentially life-saving gift of a COVID-19 vaccine. In fact, I just got my first shot of the Moderna vaccine today along with NIAID Director Anthony Fauci, HHS Secretary Alex Azar, and some front-line healthcare workers at the NIH Clinical Center. Accepting this gift is our best chance to put this pandemic behind us, as we look forward to a better new year.
Links:
Coronavirus (COVID-19) (NIH)
Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)
Dale and Betty Bumpers Vaccine Research Center (National Institute of Allergy and Infectious Diseases/NIH)
Moderna (Cambridge, MA)
Pfizer (New York, NY)
BioNTech (Mainz, Germany)
Speeding COVID-19 Drug Discovery with Quantum Dots
Posted on by Dr. Francis Collins
These round, multi-colored orbs in the illustration above may resemble SARS-CoV-2, the coronavirus responsible for COVID-19. But they’re actually lab-made nanocrystals called quantum dots. They have been specially engineered to look and, in some ways, act like the coronavirus while helping to solve a real challenge for many labs that would like to study SARS-CoV-2.
Quantum dots, which have been around since the mid-1980s, are designed with special optical properties that allow them to fluoresce when exposed to ultraviolet light. The two pictured here are about 10 nanometers in diameter, about 3,000 times smaller than the width of a human hair. The quantum dot consists of a semi-conductive cadmium selenide inner core (orange) surrounded by a zinc sulfide outer shell (teal). Molecules on its surface (yellow) allow researchers to attach the viral spike protein (purple), which SARS-CoV-2 depends on to infect human cells.
To the left is a human cell (gray) studded with the ACE2 receptors (blue) that those viral spike proteins bind to before SARS-CoV-2 enters and infects our cells. In the background, you see another spike protein-studded quantum dot. But human neutralizing antibodies (pink) are preventing that one from reaching the human cell.
Because SARS-CoV-2 is so highly infectious, basic researchers without access to specially designed biosafety facilities may be limited in their ability to study the virus. But these harmless quantum dots offer a safe workaround. While the quantum dots may bind and enter human cells just like the virus, they can’t cause an infection. They offer a quick, informative way to assess the potential of antibodies or other compounds to prevent the coronavirus from binding to our cells.
In work published in the journal ACS Nano, a team that included Kirill Gorshkov, NIH’s National Center for Advancing Translational Sciences (NCATS), Rockville, MD, along with Eunkeu Oh and Mason Wolak, Naval Research Laboratory, Washington, D.C., demonstrated how these quantum dots may serve as a useful new tool to speed the search for new COVID-19 treatments. The dots’ fluorescent glow enabled the researchers to use a microscope to observe how these viral mimics bind to ACE2 in real time, showing how SARS-CoV-2 might attach to and enter our cells, and suggesting ways to intervene.
Indeed, imagine thousands of tiny wells in which human cells are growing. Imagine adding a different candidate drug to each well; then imagine adding the loaded quantum dots to each well and using machine vision to identify the wells where the dots could not enter the cell. That’s not science fiction. That’s now.
With slightly different versions of their quantum dots, the NCATS researchers and their colleagues at the Naval Research Laboratory will now explore how other viral proteins are important for the coronavirus to infect our cells. They also can test how slight variations in the spike protein may influence SARS-CoV-2’s behavior. This work provides yet another stunning example of how scientists with widely varying expertise have banded together—using all the tools at their disposal—to forge ahead to find solutions to COVID-19.
Reference:
[1] Quantum dot-conjugated SARS-CoV-2 spike pseudo-virions enable tracking of angiotensin converting enzyme 2 binding and endocytosis. Gorshkov K, Susumu K, Chen J, Xu M, Pradhan M, Zhu W, Hu X, Breger JC, Wolak M, Oh E. ACS Nano. 2020 Sep 22;14(9):12234-12247.
Links:
What are Quantum Dots? (National Institute of Biomedical Imaging and Bioengineering/NIH)
Coronavirus (COVID-19) (NIH)
I Am Translational Science: Kirill Gorshkov (National Center for Advancing Translational Sciences/NIH)
U. S. Naval Research Laboratory (Washington, D.C.)
NIH Support: National Center for Advancing Translational Sciences
Two Studies Show COVID-19 Antibodies Persist for Months
Posted on by Dr. Francis Collins
More than 8 million people in the United States have now tested positive for COVID-19. For those who’ve recovered, many wonder if fending off SARS-CoV-2—the coronavirus that causes COVID-19—one time means their immune systems will protect them from reinfection. And, if so, how long will this “acquired immunity” last?
The early data brought hope that acquired immunity was possible. But some subsequent studies have suggested that immune protection might be short-lived. Though more research is needed, the results of two recent studies, published in the journal Science Immunology, support the early data and provide greater insight into the nature of the human immune response to this coronavirus [1,2].
The new findings show that people who survive a COVID-19 infection continue to produce protective antibodies against key parts of the virus for at least three to four months after developing their first symptoms. In contrast, some other antibody types decline more quickly. The findings offer hope that people infected with the virus will have some lasting antibody protection against re-infection, though for how long still remains to be determined.
In one of the two studies, partly funded by NIH, researchers led by Richelle Charles, Massachusetts General Hospital, Boston, sought a more detailed understanding of antibody responses following infection with SARS-CoV-2. To get a closer look, they enrolled 343 patients, most of whom had severe COVID-19 requiring hospitalization. They examined their antibody responses for up to 122 days after symptoms developed and compared them to antibodies in more than 1,500 blood samples collected before the pandemic began.
The researchers characterized the development of three types of antibodies in the blood samples. The first type was immunoglobulin G (IgG), which has the potential to confer sustained immunity. The second type was immunoglobulin A (IgA), which protects against infection on the body’s mucosal surfaces, such as those found in the respiratory and gastrointestinal tracts, and are found in high levels in tears, mucus, and other bodily secretions. The third type is immunoglobulin M (IgM), which the body produces first when fighting an infection.
They found that all three types were present by about 12 days after infection. IgA and IgM antibodies were short-lived against the spike protein that crowns SARS-CoV-2, vanishing within about two months.
The good news is that the longer-lasting IgG antibodies persisted in these same patients for up to four months, which is as long as the researchers were able to look. Levels of those IgG antibodies also served as an indicator for the presence of protective antibodies capable of neutralizing SARS-CoV-2 in the lab. Even better, that ability didn’t decline in the 75 days after the onset of symptoms. While longer-term study is needed, the findings lend support to evidence that protective antibody responses against the novel virus do persist.
The other study came to very similar conclusions. The team, led by Jennifer Gommerman and Anne-Claude Gingras, University of Toronto, Canada, profiled the same three types of antibody responses against the SARS-CoV-2 spike protein, They created the profiles using both blood and saliva taken from 439 people, not all of whom required hospitalization, who had developed COVID-19 symptoms from 3 to 115 days prior. The team then compared antibody profiles of the COVID-19 patients to those of people negative for COVID-19.
The researchers found that the antibodies against SARS-CoV-2 were readily detected in blood and saliva. IgG levels peaked about two weeks to one month after infection, and then remained stable for more than three months. Similar to the Boston team, the Canadian group saw IgA and IgM antibody levels drop rapidly.
The findings suggest that antibody tests can serve as an important tool for tracking the spread of SARS-CoV-2 through our communities. Unlike tests for the virus itself, antibody tests provide a means to detect infections that occurred sometime in the past, including those that may have been asymptomatic. The findings from the Canadian team further suggest that tests of IgG antibodies in saliva may be a convenient way to track a person’s acquired immunity to COVID-19.
Because IgA and IgM antibodies decline more quickly, testing for these different antibody types also could help to distinguish between an infection within the last two months and one that more likely occurred even earlier. Such details are important for filling in gaps in our understanding COVID-19 infections and tracking their spread in our communities.
Still, there are rare reports of individuals who survived one bout with COVID-19 and were infected with a different SARS-CoV-2 strain a few weeks later [3]. The infrequency of such reports, however, suggests that acquired immunity after SARS-CoV-2 infection is generally protective.
There remain many open questions, and answering them will require conducting larger studies with greater diversity of COVID-19 survivors. So, I’m pleased to note that the NIH’s National Cancer Institute (NCI) recently launched the NCI Serological Sciences Network for COVID19 (SeroNet), now the nation’s largest coordinated effort to characterize the immune response to COVID-19 [4].
The network was established using funds from an emergency Congressional appropriation of more than $300 million to develop, validate, improve, and implement antibody testing for COVID-19 and related technologies. With help from this network and ongoing research around the world, a clearer picture will emerge of acquired immunity that will help to control future outbreaks of COVID-19.
References:
[1] Persistence and decay of human antibody responses to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 patients. Iyer AS, Jones FK, Nodoushani A, Ryan ET, Harris JB, Charles RC, et al. Sci Immunol. 2020 Oct 8;5(52):eabe0367.
[2] Persistence of serum and saliva antibody responses to SARS-CoV-2 spike antigens in COVID-19 patients. Isho B, Abe KT, Zuo M, Durocher Y, McGeer AJ, Gommerman JL, Gingras AC, et al. Sci Immunol. 2020 Oct 8;5(52):eabe5511.
[3] What reinfections mean for COVID-19. Iwasaki A. Lancet Infect Dis, 2020 October 12. [Epub ahead of print]
[4] NIH to launch the Serological Sciences Network for COVID-19, announce grant and contract awardees. National Institutes of Health. 2020 October 8.
Links:
Coronavirus (COVID-19) (NIH)
Charles Lab (Massachusetts General Hospital, Boston)
Gingras Lab (University of Toronto, Canada)
Jennifer Gommerman (University of Toronto, Canada)
NCI Serological Sciences Network for COVID-19 (SeroNet) (National Cancer Institute/NIH)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences; National Cancer Institute
COVID-19 Vaccine Appears Well-Tolerated and Effective in Developing Antibodies in Small Study of Older Adults
Posted on by Dr. Francis Collins
It’s been truly breathtaking to watch the progress being made on a daily basis to develop safe and effective vaccines for SARS-CoV-2, the novel coronavirus that causes COVID-19. Indeed, months sooner than has ever been possible for a newly emerging infection, several promising vaccines are already working their way through Phase 3 studies, the final stage of clinical evaluation. I remain optimistic that we will have one or more vaccines that prove to be safe and effective by January 2021.
But, as encouraging as the early data have been, uncertainty has remained over whether vaccines that appear safe and effective in developing antibodies in younger adults will work as well in older people, too. It’s a critical issue given that older individuals also are at greater risk for severe or life-threatening illness if they do get sick from COVID-19.
So, I’m pleased to highlight some recent findings, published in the New England Journal of Medicine [1], from an early Phase 1 clinical trial that was expanded to include 40 adults over age 55. While we eagerly await the results of ongoing and larger studies, these early data suggest that an innovative COVID-19 vaccine co-developed by NIH’s Vaccine Research Center (VRC), in partnership with Moderna Inc., Cambridge, MA, is both well tolerated and effective in generating a strong immune response when given to adults of any age.
The centerpiece of the vaccine in question, known as mRNA-1273, is a small, non-infectious snippet of messenger RNA (mRNA). When this mRNA is injected into muscle, a person’s own body will begin to make the key viral spike protein. As the immune system detects this spike protein, it spurs the production of antibodies that may help to fend off the novel SARS-CoV-2.
Earlier findings from the NIH-supported phase 1 human clinical trial found mRNA-1273 was safe and effective in generating a vigorous immune response in people ages 18 to 55, when delivered in two injections about a month apart. Based on those findings, a large Phase 3 clinical trial is currently enrolling 30,000 volunteers, with results expected in the next few weeks [2]. But, given that immune response to many other vaccines tends to grow weaker with age, how well would this new COVID-19 vaccine work for older individuals?
To find out, a team at Kaiser Permanente Washington Health Research Institute, Seattle, and Emory University School of Medicine, Atlanta, expanded the initial Phase 1 trial to include 20 healthy volunteers ages 56 to 70 and another 20 healthy volunteers ages 71 and older. Ten volunteers in each of the two older age groups received a lower dose of the vaccine (25 micrograms) in two injections given about a month apart. The other 10 in each age group received a higher dose (100 micrograms), given on the same schedule.
Here’s what they found:
• No volunteers suffered serious adverse events. The most common adverse events were mild-to-moderate in severity and included headache, fatigue, muscle aches, chills and pain at the injection site. Those symptoms occurred most often after the second dose and in individuals receiving the higher dose of 100 micrograms.
• Volunteers showed a rapid production of protective antibodies against the spike protein following immunization. After the second injection, all participants showed a strong immune response, with production of robust binding and neutralizing antibodies against SARS-CoV-2.
• The higher dose of 100 micrograms safely produced a stronger immune response compared to the lower dose, supporting its use in larger clinical studies.
• Most importantly, the immune response observed in these older individuals was comparable to that seen previously in younger adults.
The researchers will continue to follow the volunteer trial participants of all ages for about a year to monitor the vaccine’s longer-term effects. But these findings provided support for continued testing of this promising vaccine in older adults in the ongoing Phase 3 clinical trial.
There are currently four SARS-CoV-2 vaccines in phase 3 clinical trials in the United States (though two are currently on hold). Trials of two more vaccines are expected start in the next month or two.
It is not known whether all of these vaccines will have the same vigorous immune response in older individuals that has been demonstrated for this one. But if more than one of these vaccines turns out to be safe and effective, it will be important to know about the response in various populations, so that distribution to high-risk groups can be planned accordingly.
References:
[1] Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. Anderson EJ, Rouphael NG, Widge AT, Jackson LA, Roberts PC, Makhene M, Chappell JD, Denison MR, Stevens LJ, Pruijssers AJ, McDermott AB, Flach B, Lin BC, Doria-Rose NA, O’Dell S, Schmidt SD, Corbett KS, Swanson PA 2nd, Padilla M, Neuzil KM, Bennett H, Leav B, Makowski M, Albert J, Cross K, Edara VV, Floyd K, Suthar MS, Martinez DR, Baric R, Buchanan W, Luke CJ, Phadke VK, Rostad CA, Ledgerwood JE, Graham BS, Beigel JH; mRNA-1273 Study Group. N Engl J Med. 2020 Sep 29.
[2] “Phase 3 clinical trial of investigational vaccine for COVID-19 begins.” National Institutes of Heath. July 27, 2020
Links:
Coronavirus (COVID-19) (NIH)
COVID-19 Prevention Network (National Institute of Allergy and Infectious Diseases/NIH)
Dale and Betty Bumpers Vaccine Research Center (National Institute of Allergy and Infectious Diseases/NIH)
Moderna, Inc. (Cambridge, MA)
Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis of SARS-CoV-2 Infection (COVID-19) (ClinicalTrials.gov)
NIH Support: National Institute of Allergy and Infectious Diseases
Charting a Rapid Course Toward Better COVID-19 Tests and Treatments
Posted on by Dr. Francis Collins
It is becoming apparent that our country is entering a new and troubling phase of the pandemic as SARS-CoV-2, the novel coronavirus that causes COVID-19, continues to spread across many states and reaches into both urban and rural communities. This growing community spread is hard to track because up to 40 percent of infected people seem to have no symptoms. They can pass the virus quickly and unsuspectingly to friends and family members who might be more vulnerable to becoming seriously ill. That’s why we should all be wearing masks when we go out of the house—none of us can be sure we’re not that asymptomatic carrier of the virus.
This new phase makes fast, accessible, affordable diagnostic testing a critical first step in helping people and communities. In recognition of this need, NIH’s Rapid Acceleration of Diagnostics (RADx) initiative, just initiated in late April, has issued an urgent call to the nation’s inventors and innovators to develop fast, easy-to-use tests for SARS-CoV-2, the novel coronavirus that causes COVID-19. It brought a tremendous response, and NIH selected about 100 of the best concepts for an intense one-week “shark-tank” technology evaluation process.
Moving ahead at an unprecedented pace, NIH last week announced the first RADx projects to come through the deep dive with flying colors and enter the scale-up process necessary to provide additional rapid testing capacity to the U.S. public. As part of the RADx initiative, seven biomedical technology companies will receive a total of $248.7 million in federal stimulus funding to accelerate their efforts to scale up new lab-based and point-of-care technologies.
Four of these projects will aim to bolster the nation’s lab-based COVID-19 diagnostics capacity by tens of thousands of tests per day as soon as September and by millions by the end of the year. The other three will expand point-of-care testing for COVID-19, making results more rapidly and readily available in doctor’s offices, urgent care clinics, long-term care facilities, schools, child care centers, or even at home.
This is only a start, and we expect that more RADx projects will advance in the coming months and begin scaling up for wide-scale use. In the meantime, here’s an overview of the first seven projects developed through the initiative, which NIH is carrying out in partnership with the Office of the Assistant Secretary of Health, the Biomedical Advanced Research and Development Authority, and the Department of Defense:
Point-of-Care Testing Approaches
Mesa Biotech. Hand-held testing device detects the genetic material of SARS-CoV-2. Results are read from a removable, single-use cartridge in 30 minutes.
Quidel. Test kit detects protein (viral antigen) from SARS-CoV-2. Electronic analyzers provide results within 15 minutes. The U.S. Department of Health and Human Service has identified this technology for possible use in nursing homes.
Talis Biomedical. Compact testing instrument uses a multiplexed cartridge to detect the genetic material of SARS-CoV-2 through isothermal amplification. Optical detection system delivers results in under 30 minutes.
Lab-based Testing Approaches
Ginkgo Bioworks. Automated system uses next-generation sequencing to scan patient samples for SARS-CoV-2’s genetic material. This system will be scaled up to make it possible to process tens of thousands of tests simultaneously and deliver results within one to two days. The company’s goal is to scale up to 50,000 tests per day in September and 100,000 per day by the end of 2020.
Helix OpCo. By combining bulk shipping of test kits and patient samples, automation, and next-generation sequencing of genetic material, the company’s goal is to process up to 50,000 samples per day by the end of September and 100,000 per day by the end of 2020.
Fluidigm. Microfluidics platform with the capacity to process thousands of polymerase chain reaction (PCR) tests for SARS-CoV-2 genetic material per day. The company’s goal is to scale up this platform and deploy advanced integrated fluidic chips to provide tens to hundreds of thousands of new tests per day in the fall of 2020. Most tests will use saliva.
Mammoth Biosciences. System uses innovative CRISPR gene-editing technology to detect key pieces of SARS-CoV-2 genetic material in patient samples. The company’s goal is to provide a multi-fold increase in testing capacity in commercial laboratories.
At the same time, on the treatment front, significant strides continue to be made by a remarkable public-private partnership called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). Since its formation in May, the partnership, which involves 20 biopharmaceutical companies, academic experts, and multiple federal agencies, has evaluated hundreds of therapeutic agents with potential application for COVID-19 and prioritized the most promising candidates.
Among the most exciting approaches are monoclonal antibodies (mAbs), which are biologic drugs derived from neutralizing antibodies isolated from people who’ve survived COVID-19. This week, the partnership launched two trials (one for COVID-19 inpatients, the other for COVID-19 outpatients) of a mAB called LY-CoV555, which was developed by Eli Lilly and Company, Indianapolis, IN. It was discovered by Lilly’s development partner AbCellera Biologics Inc. Vancouver, Canada, in collaboration with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID). In addition to the support from ACTIV, both of the newly launched studies also receive support for Operation Warp Speed, the government’s multi-agency effort against COVID-19.
LY-CoV555 was derived from the immune cells of one of the very first survivors of COVID-19 in the United States. It targets the spike protein on the surface of SARS-CoV-2, blocking it from attaching to human cells.
The first trial, which will look at both the safety and efficacy of the mAb for treating COVID-19, will involve about 300 individuals with mild to moderate COVID-19 who are hospitalized at facilities that are part of existing clinical trial networks. These volunteers will receive either an intravenous infusion of LY-CoV555 or a placebo solution. Five days later, their condition will be evaluated. If the initial data indicate that LY-CoV555 is safe and effective, the trial will transition immediately—and seamlessly—to enrolling an additional 700 participants with COVID-19, including some who are severely ill.
The second trial, which will evaluate how LY-CoV555 affects the early course of COVID-19, will involve 220 individuals with mild to moderate COVID-19 who don’t need to be hospitalized. In this study, participants will randomly receive either an intravenous infusion of LY-CoV555 or a placebo solution, and will be carefully monitored over the next 28 days. If the data indicate that LY-CoV555 is safe and shortens the course of COVID-19, the trial will then enroll an additional 1,780 outpatient volunteers and transition to a study that will more broadly evaluate its effectiveness.
Both trials are later expected to expand to include other experimental therapies under the same master study protocol. Master protocols allow coordinated and efficient evaluation of multiple investigational agents at multiple sites as the agents become available. These protocols are designed with a flexible, rapidly responsive framework to identify interventions that work, while reducing administrative burden and cost.
In addition, Lilly this week started a separate large-scale safety and efficacy trial to see if LY-CoV555 can be used to prevent COVID-19 in high-risk residents and staff at long-term care facilities. The study isn’t part of ACTIV.
NIH-funded researchers have been extremely busy over the past seven months, pursuing every avenue we can to detect, treat, and, ultimately, end this devasting pandemic. Far more work remains to be done, but as RADx and ACTIV exemplify, we’re making rapid progress through collaboration and a strong, sustained investment in scientific innovation.
Links:
Coronavirus (COVID-19) (NIH)
Rapid Acceleration of Diagnostics (RADx)
Video: NIH RADx Delivering New COVID-19 Testing Technologies to Meet U.S. Demand (YouTube)
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)
Explaining Operation Warp Speed (U.S. Department of Health and Human Resources/Washington, D.C.)
“NIH delivering new COVID-19 testing technologies to meet U.S. demand,” NIH news release,” July 31, 2020.
“NIH launches clinical trial to test antibody treatment in hospitalized COVID-19 patients,” NIH new release, August 4, 2020.
“NIH clinical trial to test antibodies and other experimental therapeutics for mild and moderate COVID-19,” NIH news release, August 4, 2020.
What We Know About COVID-19’s Effects on Child and Maternal Health
Posted on by Dr. Francis Collins
There’s been a lot of focus, and rightly so, on why older adults and adults with chronic disease appear to be at increased risk for coronavirus disease 2019 (COVID-19). Not nearly as much seems to be known about children and COVID-19.
For example, why does SARS-CoV-2, the novel coronavirus that causes COVID-19, seem to affect children differently than adults? What is the psychosocial impact of the pandemic on our youngsters? Are kids as infectious as adults?
A lot of interesting research in this area has been published recently. That includes the results of a large study in South Korea in which researchers traced the person-to-person spread of SARS-CoV-2 in the early days of the pandemic. The researchers found children younger than age 10 spread the virus to others much less often than adults do, though the risk is not zero. But children age 10 to 19 were found to be just as infectious as adults. That obviously has consequences for the current debate about opening the schools.
To get some science-based answers to these and other questions, I recently turned to one of the world’s leading child health researchers: Dr. Diana Bianchi, Director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Dr. Bianchi is a pediatrician with expertise in newborn medicine, neonatology, and reproductive genetics. Here’s a condensed transcript of our chat, which took place via videoconference, with Diana linking in from Boston and me from my home in Chevy Chase, MD:
Collins: What is the overall risk of children getting COVID-19? We initially heard they’re at very low risk. [NOTE: Since the recording of this interview, new data has emerged from state health departments that suggest that as much as 10 percent of new cases of COVID-19 occur in children.]
Bianchi: Biological factors certainly play some role. We know that the virus often enters the body via cells in the nasal passage. A recent study showed that, compared to adults, children’s nasal cells have less of the ACE2 receptor, which the virus attaches to and uses to infect cells. In children, the virus probably has less of an opportunity to grab onto cells and get into the upper respiratory tract.
Importantly, social reasons also play a role in that low percentage. Children have largely been socially isolated since March, when many schools shut down. By and large, young kids have been either home or playing in their backyards.
Collins: If kids do get infected with SARS-CoV-2, the virus that causes COVID-19, what kind of symptoms are displayed?
Bianchi: Children tend to be affected mildly. Relatively few children end up in intensive care units. The most common symptoms are: fever, in about 60 percent of children; cough; and a mild respiratory illness. It’s a different clinical presentation. Children seem to be more prone to vomiting, diarrhea, severe abdominal pain, and other gastrointestinal problems.
Collins: Are children as infectious as adults?
Bianchi: We suspect that older kids probably are. A recently published meta-analysis, or systematic review of the medical literature, also found about 20 percent of infected kids are asymptomatic. There are probably a lot of kids out there who can potentially infect others.
Collins: Do you see a path forward here for schools in the fall?
Bianchi: I think the key word is flexibility. We must remain flexible in the months ahead. Children have struggled from being out of school, and it’s not just the educational loss. It’s the whole support system, which includes the opportunity to exercise. It includes the opportunity to have teachers and school staff looking objectively at the kids to see if they are psychologically well.
The closing of schools has also exacerbated disparities. Schools provide meals for many kids in need, and some have had a lot of food insecurity for the past several months. Not to mention kids in homeless situations often don’t have access to the internet and other learning tools. So, on the whole, being in school is better for children than not being there. That’s how most pediatricians see it. However, we don’t want to put children at risk for getting sick.
Collins: Can you say a little bit more about the consequences, particularly for young children, of being away from their usual areas of social interaction? That’s true this summer as well. Camps that normally would be a place where lots of kids would congregate have either been cancelled or are being conducted in a very different way.
Bianchi: Thus far, most of the published information that we have has really been on the infection and the clinical presentations. Ultimately, I think there will be a lot of information about the behavioral and developmental consequences of not being exposed to other children. I think that older children are also really suffering from not having a daily structure, for example, through sports.
For younger children, they need to learn how to socialize. There are advantages to being with your parents. But there are a lot of social skills that need to be learned without them. People talk about the one-eyed babysitter, YouTube. The American Academy of Pediatrics has issued recommendations for limiting screen time. That’s gone out the window. I’ve talked with a lot of my staff members who are struggling with this balance between educating or entertaining their children and having so-called quality time, and the responsibility to do their jobs.
Collins: What about children with disabilities? Are they in a particularly vulnerable place?
Bianchi: Absolutely. Sadly, we don’t hear a lot about children with disabilities as a vulnerable population. Neither do we hear a lot about the consequences of them not receiving needed services. So many children with disabilities rely on people coming into their homes, whether it’s to help with respiratory care or to provide physical or speech therapy. Many of these home visits are on hold during the pandemic, and that can cause serious problems. For example, you can’t suction a trachea remotely. Of course, you can do speech therapy remotely, but that’s not ideal for two reasons. First, face-to-face interactions are still better, and, secondly, disparities can factor into the equation. Not all kids with disabilities have access to the internet or all the right equipment for online learning.
Collins: Tell me a little bit more about a rare form of consequences from COVID-19, this condition called MIS-C, Multi-System Inflammatory Syndrome of Children. I don’t think anybody knew anything about that until just a couple of months ago.
Bianchi: Even though there were published reports of children infected with SARS-CoV-2 in China in January, we didn’t hear until April about this serious new inflammatory condition. Interestingly, none of the children infected with SARS-CoV-2 in China or Japan are reported to have developed MIS-C. It seemed to be something that was on the European side, predominantly the United Kingdom, Italy, and France. And then, starting in April and May, it was seen in New York and the northeastern United States.
The reason it’s of concern is that many of these children are gravely ill. I mentioned that most children have a mild illness, but the 0.5 percent who get the MIS-C are seriously ill. Almost all require admission to the ICU. The scary thing is they can turn on a dime. They present with more of a prolonged fever. They can have very severe abdominal pain. In some cases, children have been thought to have appendicitis, but they don’t. They have serious cardiac issues and go into shock.
The good news is the majority survive. Many require ventilators and blood-pressure support. But they do respond to treatment. They tend to get out of the hospital in about a week. However, in two studies of MIS-C recently published in New England Journal of Medicine, six children died out of 300 children. So that’s what we want to avoid.
Collins: In terms of the cause, there’s something puzzling about MIS-C. It doesn’t seem to be a direct result of the viral infection. It seems to come on somewhat later, almost like there’s some autoimmune response.
Bianchi: Yes, that’s right. MIS-C does tend to occur, on an average, three to four weeks later. The NIH hosted a conference a couple weeks ago where the top immunologists in the world were talking about MIS-C, and everybody has their piece of the elephant in terms of a hypothesis. We don’t really know right now, but it does seem to be associated with some sort of exuberant, post-infectious inflammatory response.
Is it due to the fact that the virus is still hiding somewhere in the body? Is the body reacting to the virus with excessive production of antibodies? We don’t know. That will be determined, hopefully, within weeks or months.
Collins: And I know that your institute is taking a leading role in studying MIS-C.
Bianchi: Yes. Very shortly after the first cases of MIS-C were being described in the United States, you asked me and Gary Gibbons, director of NIH’s National Heart Lung and Blood Institute, to cochair a taskforce to develop a study designed to address MIS-C. Staff at both institutes have been working, in collaboration with NIH’s National Institute of Allergy and Infectious Diseases, to come up with the best possible way to approach this public health problem.
The study consists of a core group of kids who are in the hospital being treated for MIS-C. We’re obtaining biospecimens and are committed to a central platform and data-sharing. There’s an arm of the study that’s looking at long-term issues. These kids have transient coronary artery dilation. They have a myocarditis. They have markers of heart failure. What does that imply long-term for the function of their hearts?
We will also be working with several existing networks to identify markers suggesting that a certain child is at risk. Is it an underlying immune issue, or is it ethnic background? Is it this a European genomic variant? Exactly what should we be concerned about?
Collins: Let me touch on the genomics part of this for a minute, and that requires a brief description. The SARS-CoV-2 novel coronavirus is crowned in spiky proteins that attach to our cells before infecting them. These spike proteins are made of many amino acids, and their precise sequential order can sometimes shift in subtle ways.
Within that sequential order at amino acid 614, a shift has been discovered. The original Chinese isolate, called the D version, had aspartic acid there. It seems the virus that spread from Asia to the U.S. West Coast also has aspartic acid in that position. But the virus that traveled to Italy and then to the East Coast of the U.S. has a glycine there. It’s called the G version.
There’s been a lot of debate about whether this change really matters. More data are starting to appear suggesting that the G version may be more infectious than the D version, although I’ve seen no real evidence of any difference in severity between the two.
Of course, if the change turned out to be playing a role in MIS-C, you would expect not to have seen so many cases on the West Coast. Has anyone looked to see if kids with the D version of the virus ever get MIS-C?
Bianchi: It hasn’t been reported. You could say that maybe we don’t get all the information from China. But we do get it from Japan. In Japan, they’ve had the D version, and they haven’t had MIS-C.
Collins: Let’s talk about expectant mothers. What is the special impact of COVID-19 on them?
Bianchi: Recently, a lot of information has come out about pregnant women and the developing fetus. A recent report from the Centers for Disease Control and Prevention suggested that pregnant women are at a greatly increased risk of hospitalization. However, the report didn’t divide out hospitalizations that would be expected for delivering a baby from hospitalizations related to illness. But the report did show that pregnant women are at a higher risk of needing respiratory support and having serious illness, particularly if there is an underlying chronic condition, such as chronic lung disease, diabetes or hypertension.
Collins: Do we know the risk of the mother transmitting the coronavirus to the fetus?
Bianchi: What we know so far is the risk of transmission from mother to baby appears to be small. Now, that’s based on the fact that available studies seem to suggest that the ACE2 receptor that the virus uses to bind to our cells, is not expressed in third trimester placental tissue. That doesn’t mean it’s not expressed earlier in gestation. The placenta is so dynamic in terms of gene expression.
What we do know is there’s a lot of ACE2 expression in the blood vessels. An interesting recent study showed in the third trimester placenta, the blood vessels had taken a hit. There was actual blood vessel damage. There was evidence of decreased oxygenation in the placenta. We don’t know the long-term consequences for the baby, but the placentas did not look healthy.
Collins: I have a friend whose daughter recently was ready to deliver her baby. As part of preparing for labor, she had a COVID-19 test. To her surprise and dismay, she was positive, even though she had no symptoms. She went ahead with the delivery, but then the baby was separated from her for a time because of a concern about the mother transmitting the virus to her newborn. Is separation widely recommended?
Bianchi: I think most hospitals are softening on this. [NOTE: The American Academy of Pediatrics recently issued revised recommendations about labor and delivery, as well as about breastfeeding, during COVID-19]
In the beginning, hospitals took a hard line. For example, no support people were allowed into the delivery room. So, women were having more home deliveries, which are far more dangerous, or signing up to give birth at hospitals that allowed support people.
Now more hospitals are allowing a support person in the room during delivery. But, in general, they are recommending that the mother and the support person get tested. If they’re negative, everything’s fine. If the support person is positive, he or she’s not allowed to come in. If the mother is positive, the baby is separated, generally, for testing. In many hospitals, mothers are given the option of reuniting with the baby.
There’s also been a general discussion about mothers who test positive breastfeeding. The more conservative recommendation is to pump the milk and allow somebody else to bottle-feed the baby while the mother recovers from the infection. I should also mention a recent meta-analysis in the United Kingdom. It suggested that a cesarean section delivery is not needed because of SARS-CoV-2 positivity alone. It also found there’s no reason for SARS-CoV-2 positive women not to breast feed.
Collins: Well, Diana, thank you so much for sharing your knowledge. If there’s one thing you wanted parents to take away from this conversation, what would that be?
Bianchi: Well, I think it’s natural to be concerned during a pandemic. But I think parents should be generally reassuring to their children. We’ll get through this. However, I would also say that if a parent notices something unusual going on with a child—skin rashes, the so-called blue COVID toes, or a prolonged fever—don’t mess around. Get your child medical attention as soon as possible. Bad things can happen very quickly to children infected with this virus.
For the expectant parents, hopefully, their obstetricians are counseling them about the fact that they are at high risk. I think that women with chronic conditions really need to be proactive. If they’re not feeling well, they need to go to the emergency room. Again, things can happen quickly with this virus.
But the good news is the babies seem to do very well. There’s no evidence of birth defects so far, and very limited evidence, if at all, of vertical transmission. I think they can feel good about their babies. They need to pay attention to themselves.
Collins: Thank you, Diana, for ending on those wise words.
Bianchi: Thanks, Francis.
Links:
Coronavirus (COVID-19) (NIH)
Diana W. Bianchi, MD, Biosketch of the NICHD Director (Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH)
Responding to COVID-19, Director’s Corner, NICHD, June 3, 2020
National Child & Maternal Health Education Program (NICHD)
Pregnancy (NICHD)
Researchers Publish Encouraging Early Data on COVID-19 Vaccine
Posted on by Dr. Francis Collins
People all around the globe are anxiously awaiting development of a safe, effective vaccine to protect against the deadly threat of coronavirus disease 2019 (COVID-19). Evidence is growing that biomedical research is on track to provide such help, and to do so in record time.
Just two days ago, in a paper in the New England Journal of Medicine [1], researchers presented encouraging results from the vaccine that’s furthest along in U.S. human testing: an innovative approach from NIH’s Vaccine Research Center (VRC), in partnership with Moderna Inc., Cambridge, MA [1]. The centerpiece of this vaccine is a small, non-infectious snippet of messenger RNA (mRNA). Injecting this mRNA into muscle will spur a person’s own body to make a key viral protein, which, in turn, will encourage the production of protective antibodies against SARS-CoV-2—the novel coronavirus that causes COVID-19.
While it generally takes five to 10 years to develop a vaccine against a new infectious agent, we simply don’t have that time with a pandemic as devastating as COVID-19. Upon learning of the COVID-19 outbreak in China early this year, and seeing the genome sequence of SARS-CoV-2 appear on the internet, researchers with NIH’s National Institute of Allergy and Infectious Diseases (NIAID) carefully studied the viral instructions, focusing on the portion that codes for a spike protein that the virus uses to bind to and infect human cells.
Because of their experience with the original SARS virus back in the 2000s, they thought a similar approach to vaccine development would work and modified an existing design to reflect the different sequence of the SARS-CoV-2 spike protein. Literally within days, they had created a vaccine in the lab. They then went on to work with Moderna, a biotech firm that’s produced personalized cancer vaccines. All told, it took just 66 days from the time the genome sequence was made available in January to the start of the first-in-human study described in the new peer-reviewed paper.
In the NIH-supported phase 1 human clinical trial, researchers found the vaccine, called mRNA-1273, to be safe and generally well tolerated. Importantly, human volunteers also developed significant quantities of neutralizing antibodies that target the virus in the right place to block it from infecting their cells.
Conducted at Kaiser Permanente Washington Health Research Institute, Seattle; and Emory University School of Medicine, Atlanta, the trial led by Kaiser Permanente’s Lisa Jackson involved healthy adult volunteers. Each volunteer received two vaccinations in the upper arm at one of three doses, given approximately one month apart.
The volunteers will be tracked for a full year, allowing researchers to monitor their health and antibody production. However, the recently published paper provides interim data on the phase 1 trial’s first 45 participants, ages 18 to 55, for the first 57 days after their second vaccination. The data revealed:
• No volunteers suffered serious adverse events.
• Optimal dose to elicit high levels of neutralizing antibody activity, while also protecting patient safety, appears to be 100 micrograms. Doses administered in the phase 1 trial were either 25, 100, or 250 micrograms.
• More than half of the volunteers reported fatigue, headache, chills, muscle aches, or pain at the injection site. Those symptoms were most common after the second vaccination and in volunteers who received the highest vaccine dose. That dose will not be used in larger trials.
• Two doses of 100 micrograms of the vaccine prompted a robust immune response, which was last measured 43 days after the second dose. These responses were actually above the average levels seen in blood samples from people who had recovered from COVID-19.
These encouraging results are being used to inform the next rounds of human testing of the mRNA-1273 vaccine. A phase 2 clinical trial is already well on its way to recruiting 600 healthy adults.This study will continue to profile the vaccine’s safety, as well as its ability to trigger an immune response.
Meanwhile, later this month, a phase 3 clinical trial will begin enrolling 30,000 volunteers, with particular focus on recruitment in regions and populations that have been particularly hard hit by the virus.
The design of that trial, referred to as a “master protocol,” had major contributions from the Accelerating COVID-19 Therapeutic Interventions and Vaccine (ACTIV) initiative, a remarkable public-private partnership involving 20 biopharmaceutical companies, academic experts, and multiple federal agencies. Now, a coordinated effort across the U.S. government, called Operation Warp Speed, is supporting rapid conduct of these clinical trials and making sure that millions of doses of any successful vaccine will be ready if the vaccine proves save and effective.
Results of this first phase 3 trial are expected in a few months. If you are interested in volunteering for these or other prevention trials, please check out NIH’s new COVID-19 clinical trials network.
There’s still a lot of work that remains to be done, and anything can happen en route to the finish line. But by pulling together, and leaning on the very best science, I am confident that we will be able rise to the challenge of ending this pandemic that has devastated so many lives.
Reference:
[1] A SARS-CoV-2 mRNA Vaccine—Preliminary Report. Jackson LA, Anderson EJ, Rouphael NG, Ledgerwood JE, Graham BS, Beigel JH, et al. NEJM. 2020 July 14. [Publication ahead of print]
Links:
Coronavirus (COVID-19) (NIH)
Dale and Betty Bumpers Vaccine Research Center (National Institute of Allergy and Infectious Diseases/NIH)
Moderna, Inc. (Cambridge, MA)
Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis of SARS-CoV-2 Infection (COVID-19) (ClinicalTrials.gov)
“NIH Launches Clinical Trials Network to Test COVID-19 Vaccines and Other Prevention Tools,” NIAID News Release, NIH, July 8, 2020.
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)
Explaining Operation Warp Speed (U.S. Department of Health and Human Services, Washington, DC)
NIH Support: National Institute of Allergy and Infectious Diseases
Study in Primates Finds Acquired Immunity Prevents COVID-19 Reinfections
Posted on by Dr. Francis Collins
There have been rare reports of people recovering from infection with SARS-CoV-2, the novel coronavirus that causes COVID-19, only to test positive a second time. Such results might be explained by reports that the virus can linger in our systems. Yet some important questions remain: Is it possible that people could beat this virus only to get reinfected a short time later? How long does immunity last after infection? And what can we expect about the duration of protection from a vaccine?
A recent study of rhesus macaques, which are among our close primate relatives, offers relevant insights into the first question. In a paper published in the journal Science, researchers found that after macaques recover from mild SARS-CoV-2 infection, they are protected from reinfection—at least for a while.
In work conducted in the lab of Chuan Qin, Peking Union Medical College, Beijing, China, six macaques were exposed to SARS-CoV-2. Following infection, the animals developed mild-to-moderate illness, including pneumonia and evidence of active infection in their respiratory and gastrointestinal tracts. Twenty-eight days later, when the macaques had cleared the infection and started recovering, four animals were re-exposed to the same strain of SARS-CoV-2. The other two served as controls, with researchers monitoring their continued recovery.
Qin’s team noted that after the second SARS-CoV-2 exposure, the four macaques developed a transient fever that had not been seen after their first infection. No other signs of reinfection were observed or detected in chest X-rays, and the animals tested negative for active virus over a two-week period.
While more study is needed to understand details of the immune responses, researchers did detect a reassuring appearance of antibodies specific to the SARS-CoV-2 spike protein in the macaques over the course of the first infection. The spike protein is what the virus uses to attach to macaque and human cells before infecting them.
Of interest, levels of those neutralizing antibodies were even higher two weeks after the second viral challenge than they were two weeks after the initial exposure. However, researchers note that it remains unclear which factors specifically were responsible for the observed protection against reinfection, and apparently the first exposure was sufficient.
Since the second viral challenge took place just 28 days after the first infection, this study provides a rather limited window into broad landscape of SARS-CoV-2 infection and recovery. Consequently, it will be important to determine to what extent a first infection might afford protection over the course of months and even years. Also, because the macaques in this study developed only mild-to-moderate COVID-19, more research is needed to investigate what happens after recovery from more severe COVID-19.
Of course, macaques are not humans. Nevertheless, the findings lend hope that COVID-19 patients who develop acquired immunity may be at low risk for reinfection, at least in the short term. Additional studies are underway to track people who came down with COVID-19 in New York during March and April to see if any experience reinfection. By the end of this year, we should have better answers.
Reference:
[1] Primary exposure to SARS-CoV-2 protects against reinfection in rhesus macaques. Deng W, Bao L, Liu J, et al. Science. 2020 Jul 2. [Published online ahead of print].
Links:
Coronavirus (COVID-19) (NIH)
Qin Lab (Peking Union Medical College, Beijing, China)
Meet the Researcher Leading NIH’s COVID-19 Vaccine Development Efforts
Posted on by Dr. Francis Collins
A safe, effective vaccine is the ultimate tool needed to end the coronavirus disease 2019 (COVID-19) pandemic. Biomedical researchers are making progress every day towards such a vaccine, whether it’s devising innovative technologies or figuring out ways to speed human testing. In fact, just this week, NIH’s National Institute of Allergy and Infectious Diseases (NIAID) established a new clinical trials network that will enroll tens of thousands of volunteers in large-scale clinical trials testing a variety of investigational COVID-19 vaccines.
Among the vaccines moving rapidly through the development pipeline is one developed by NIAID’s Dale and Betty Bumpers Vaccine Research Center (VRC), in partnership with Moderna, Inc., Cambridge, MA. So, I couldn’t think of a better person to give us a quick overview of the COVID-19 vaccine research landscape than NIH’s Dr. John Mascola, who is Director of the VRC. Our recent conversation took place via videoconference, with John linking in from his home in Rockville, MD, and me from my place in nearby Chevy Chase. Here’s a condensed transcript of our chat:
Collins: Vaccines have been around since Edward Jenner and smallpox in the late 1700s. But how does a vaccine actually work to protect someone from infection?
Mascola: The immune system works by seeing something that’s foreign and then responding to it. Vaccines depend on the fact that if the immune system has seen a foreign protein or entity once, the second time the immune response will be much brisker. So, with these principles in mind, we vaccinate using part of a viral protein that the immune system will recognize as foreign. The response to this viral protein, or antigen, calls in specialized T and B cells, the so-called memory cells, and they remember the encounter. When you get exposed to the real thing, the immune system is already prepared. Its response is so rapid that you clear the virus before you get sick.
Collins: What are the steps involved in developing a vaccine?
Mascola: One can’t make a vaccine, generally speaking, without knowing something about the virus. We need to understand its surface proteins. We need to understand how the immune system sees the virus. Once that knowledge exists, we can make a candidate vaccine in the laboratory pretty quickly. We then transfer the vaccine to a manufacturing facility, called a pilot plant, that makes clinical grade material for testing. When enough testable material is available, we do a first-in-human study, often at our vaccine clinic at the NIH Clinical Center.
If those tests look promising, the next big step is finding a pharmaceutical partner to make the vaccine at large scale, seek regulatory approval, and distribute it commercially. That usually takes a while. So, from start to finish, the process often takes five or more years.
Collins: With this global crisis, we obviously don’t have five years to wait. Tell us about what the VRC started to do as soon as you learned about the outbreak in Wuhan, China.
Mascola: Sure. It’s a fascinating story. We had been talking with NIAID Director Dr. Anthony Fauci and our colleagues about how to prepare for the next pandemic. Pretty high on our list were coronaviruses, having already worked on past outbreaks of SARS and MERS [other respiratory diseases caused by coronaviruses]. So, we studied coronaviruses and focused on the unique spike protein crowning their surfaces. We designed a vaccine that presented the spike protein to the immune system.
Collins: Knowing that the spike protein was likely your antigen, what was your approach to designing the vaccine?
Mascola: Our approach was a nucleic acid-based vaccine. I’m referring to vaccines that are based on genetic material, either DNA or RNA. It’s this type of vaccine that can be moved most rapidly into the clinic for initial testing.
When we learned of the outbreak in Wuhan, we simply accessed the nucleic acid sequence of SARS-CoV-2, the novel coronavirus that causes COVID-19. Most of the sequence was on a server from Chinese investigators. We looked at the spike sequence and built that into an RNA vaccine. This is called in silico vaccine design. Because of our experience with the original SARS back in the 2000s, we knew its sequence and we knew this approach worked. We simply modified the vaccine design to the sequence of the spike protein of SARS-CoV-2. Literally within days, we started making the vaccine in the lab.
At the same time, we worked with a biotechnology company called Moderna that creates personalized cancer vaccines. From the time the sequence was made available in early January to the start of the first in-human study, it was about 65 days.
Collins: Wow! Has there ever been a vaccine developed in 65 days?
Mascola: I don’t think so. There are a lot of firsts with COVID, and vaccine development is one of them.
Collins: For the volunteers who enrolled in the phase 1 study, what was actually in the syringe?
Mascola: The syringe included messenger RNA (mRNA), the encoded instructions for making a specific protein, in this case the spike protein. The mRNA is formulated in a lipid nanoparticle shell. The reason is mRNA is less stable than DNA, and it doesn’t like to hang around in a test tube where enzymes can break it down. But if one formulates it just right into a nanoparticle, the mRNA is protected. Furthermore, that protective particle allows one to inject it into muscle and facilitates the uptake of the mRNA into the muscle cells. The cells translate the mRNA into spike proteins, and the immune system sees them and mounts a response.
Collins: Do muscle cells know how to take that protein and put it on their cell surfaces, where the immune system can see it?
Mascola: They do if the mRNA is engineered just the right way. We’ve been doing this with DNA for a long time. With mRNA, the advantage is that it just has to get into the cell [not into the nucleus of the cell as it does for DNA]. But it took about a decade of work to figure out how to do nucleotide silencing, which allows the cell to see the mRNA, not destroy it, and actually treat it as a normal piece of mRNA to translate into protein. Once that was figured out, it becomes pretty easy to make any specific vaccine.
Collins: That’s really an amazing part of the science. While it seems like this all happened in a blink of an eye, 65 days, it was built on years of basic science work to understand how cells treat mRNA. What’s the status of the vaccine right now?
Mascola: Early data from the phase 1 study are very encouraging. There’s a manuscript in preparation that should be out shortly showing that the vaccine was safe. It induced a very robust immune response to that spike protein. In particular, we looked for neutralizing antibodies, which are the ones that attach to the spike, blocking the virus from binding to a cell. There’s a general principle in vaccine development: if the immune system generates neutralizing antibodies, that’s a very good sign.
Collins: You’d be the first to say that you’re not done yet. Even though those are good signs, that doesn’t prove that this vaccine will work. What else do you need to know?
Mascola: The only real way to learn if a vaccine works is to test it in people. We break clinical studies into phases 1, 2, and 3. Phase 1 has already been done to evaluate safety. Phase 2 is a larger evaluation of safety and immune response. That’s ongoing and has enrolled 500 or 600 people, which is good. The plan for the phase 3 study will be to start in July. Again, that’s incredibly fast, considering that we didn’t even know this virus existed until January.
Collins: How many people do you need to study in a phase 3 trial?
Mascola: We’re thinking 20,000 or 30,000.
Collins: And half get the vaccine and half get a placebo?
Mascola: Sometimes it can be done differently, but the classic approach is half placebo, half vaccine.
Collins: We’ve been talking about the VRC-Moderna nucleic acid vaccine. But there are others that are coming along pretty quickly. What other strategies are being employed, and what are their timetables?
Mascola: There are many dozens of vaccines under development. The response has been extraordinary by academic groups, biotech companies, pharmaceutical companies, and NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership. I don’t think I’ve ever seen so much activity in a vaccine space moving ahead at such a rapid clip.
As far as being ready for advanced clinical trials, there are a just handful and they involve different types of vaccines. At least three nucleic acid vaccines are in clinical trials. There are also two vaccines that use proteins, which is a more classic approach.
In addition, there are several vaccines based on a viral vector. To make these, one puts the genes for the spike protein inside an adenovirus, which is an innocuous cold virus, and injects it into muscle. In regard to phase 3 trials, there are maybe three or four vaccines that could be formally in such tests by the fall.
Collins: How is it possible to do this so much more rapidly than in the past, without imposing risks?
Mascola: It’s a really important question, Francis. A number of things are being done in parallel, and that wouldn’t usually be the case. We can get a vaccine into a first-in-human study much more quickly because of time-saving technologies.
But the real important point is that for the phase 3 trial, there are no timesavers. One must enroll 30,000 people and watch them over months in a very rigorous, placebo-controlled environment. The NIH has stood up what’s called a Data Safety Monitoring Board for all the trials. That’s an independent group of investigators that will review all vaccine trial data periodically. They can see what the data are showing: Should the trial be stopped early because the vaccine is working? Is there a safety signal that raises concern?
While the phase 3 trial is going on, the U.S. government also will be funding large-scale manufacture of the vaccine. Traditionally, you would do the vaccine trial, wait until it’s all done, and analyze the data. If it worked, you’d build a vaccine plant to make enough material, which takes two or three years, and then go to the Food and Drug Administration (FDA) for regulatory approval.
Everything here is being done in parallel. So, if the vaccine works, it’s already in supply. And we have been engaging the FDA to get real-time feedback. That does save a lot of time.
Collins: Is it possible that we’ll manufacture a whole lot of doses that may have to be thrown out if the vaccine doesn’t work?
Mascola: It certainly is possible. One would like to think that for coronaviruses, vaccines are likely to work, in part because the natural immune response clears them. People get quite sick, but eventually the immune system clears the virus. So, if we can prime it with a vaccine, there is reason to believe vaccines should work.
Collins: If the vaccine does work, will this be for lifelong prevention of COVID-19? Or will this be like the flu, where the virus keeps changing and new versions of the vaccine are needed every year?
Mascola: From what we know about coronaviruses, we think it’s likely COVID-19 is not like the flu. Coronaviruses do have some mutation rate, but the data suggest it’s not as rapid as influenza. If we’re fortunate, the vaccine won’t need to be changed. Still, there’s the matter of whether the immunity lasts for a year, five years, or 10 years. That we don’t know without more data.
Collins: Do we know for sure that somebody who has had COVID-19 can’t get it again a few months later?
Mascola: We don’t know yet. To get the answer, we must do natural history studies, where we follow people who’ve been infected and see if their risk of getting the infection is much lower. Although classically in virology, if your immune system shows neutralizing antibodies to a virus, it’s very likely you have some level of immunity.
What’s a bit tricky is there are people who get very mild symptoms of COVID-19. Does that mean their immune system only saw a little bit of the viral antigen and didn’t respond very robustly? We’re not sure that everyone who gets an infection is equally protected. That’s going to require a natural history study, which will take about a year of follow-up to get the answers.
Collins: Let’s go back to trials that need to happen this summer. You talked about 20,000 to 30,000 people needing to volunteer just for one vaccine. Whom do you want to volunteer?
Mascola: The idea with a phase 3 trial is to have a broad spectrum of participation. To conduct a trial of 30,000 people is an enormous logistical operation, but it has been done for the rotavirus and HPV vaccines. When you get to phase 3, you don’t want to enroll just healthy adults. You want to enroll people who are representative of the diverse population that you want to protect.
Collins: Do you want to enrich for high-risk populations? They’re the ones for whom we hope the vaccine will provide greatest benefit: for example, older people with chronic illnesses, African Americans, and Hispanics.
Mascola: Absolutely. We want to make sure that we can feel comfortable to recommend the vaccine to at-risk populations.
Collins: Some people have floated another possibility. They ask why do we need expensive, long-term clinical trials with tens of thousands of people? Couldn’t we do a human challenge trial in which we give the vaccine to some healthy, young volunteers, wait a couple of weeks, and then intentionally expose them to SARS-CoV-2. If they don’t get sick, we’re done. Are challenge studies a good idea for COVID-19?
Mascola: Not right now. First, one has to make a challenge stock of the SARS-CoV-2 that’s not too pathogenic. We don’t want to make something in the lab that causes people to get severe pneumonia. Also, for challenge studies, it would be preferable to have a very effective small drug or antibody treatment on hand. If someone were to get sick, you could take care of the infection pretty readily with the treatments. We don’t have curative treatments, so the current thinking is we’re not there yet for COVID-19 challenge studies [1]. If you look at our accelerated timeline, formal vaccine trials still may be the fastest and safest way to get the answers.
Collins: I’m glad you’re doing it the other way, John. It’s going to take a lot of effort. You’re going to have to go somewhere where there is still ongoing spread, otherwise you won’t know if the vaccine works or not. That’s going to be tricky.
Mascola: Yes. How do we know where to test the vaccine? We are using predictive analytics, which is just a fancy way of saying that we are trying to predict where in the country there will be ongoing transmission. If we can get really good at it, we’ll have real-time data to say transmission is ongoing in a certain area. We can vaccinate in that community, while also possibly protecting people most at risk.
Collins: John, this conversation has been really informative. What’s your most optimistic view about when we might have a COVID-19 vaccine that’s safe and effective enough to distribute to the public?
Mascola: An optimistic scenario would be that we get an answer in the phase 3 trial towards the end of this year. We have scaled up the production in parallel, so the vaccine should be available in great supply. We still must allow for the FDA to review the data and be comfortable with licensing the vaccine. Then we must factor in a little time for distributing and recommending that people get the vaccine.
Collins: Well, it’s wonderful to have someone with your skills, experience, and vision taking such a leading role, along with your many colleagues at the Vaccine Research Center. People like Kizzmekia Corbett, Barney Graham, and all the others who are a part of this amazing team that you’ve put together, overseen by Dr. Fauci.
While there is still a ways to go, we can take pride in how far we have come since this virus emerged just about six months ago. In my 27 years at NIH, I’ve never seen anything quite like this. There’s been a willingness among people to set aside all kinds of other concerns. They’ve gathered around the same table, worked on vaccine design and implementation, and gotten out there in the real world to launch clinical trials.
John, thank you for what you are doing 24/7 to make this kind of progress possible. We’re all watching, hoping, and praying that this will turn out to be the answer that people desperately need after such a terribly difficult time so far in 2020. I believe 2021 will be a very different kind of experience, largely because of the vaccine science that we’ve been talking about today.
Mascola: Thank you so much, Francis. And thanks for recognizing all the people behind the scenes who are making this happen. They’re working really hard!
Reference:
[1] Accelerating Development of SARS-CoV-2 Vaccines—The Role for Controlled Human Infection Models. Deming ME, Michael, NL, Robb M, Cohen MS, Neuzil KM. N Engl J Med. 2020 July 1. [Epub ahead of print].
Links:
Coronavirus (COVID-19) (NIH)
John R. Mascola (National Institute of Allergy and Infectious Diseases/NIH)
Novel Vaccine Technologies for the 21st Century. Mascola JR, Fauci AS. Nat Rev Immunol. 2020 Feb;20(2):87-88.
Vaccine Research Center (NIAID/NIH)
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)
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