Posted on by Dr. Francis Collins
For the millions of Americans now eligible to receive the Pfizer or Moderna COVID-19 vaccines, it’s recommended that everyone get two shots. The first dose of these mRNA vaccines trains the immune system to recognize and attack the spike protein on the surface of SARS-CoV-2, the virus that causes COVID-19. The second dose, administered a few weeks later, boosts antibody levels to afford even better protection. People who’ve recovered from COVID-19 also should definitely get vaccinated to maximize protection against possible re-infection. But, because they already have some natural immunity, would just one shot do the trick? Or do they still need two?
A small, NIH-supported study, published as a pre-print on medRxiv, offers some early data on this important question . The findings show that immune response to the first vaccine dose in a person who’s already had COVID-19 is equal to, or in some cases better, than the response to the second dose in a person who hasn’t had COVID-19. While much more research is needed—and I am definitely not suggesting a change in the current recommendations right now—the results raise the possibility that one dose might be enough for someone who’s been infected with SARS-CoV-2 and already generated antibodies against the virus.
These findings come from a research team led by Florian Krammer and Viviana Simon, Icahn School of Medicine at Mount Sinai, New York. The researchers reasoned that for folks whose bodies have already produced antibodies following a COVID-19 infection, the first shot might act similarly to the second one in someone who hadn’t had the virus before. In fact, there was some anecdotal evidence suggesting that previously infected people were experiencing stronger evidence of an active immune response (sore arm, fever, chills, fatigue) than never-infected individuals after getting their first shots.
What did the antibodies show? To find out, the researchers enlisted the help of 109 people who’d received their first dose of mRNA vaccines made by either Pfizer or Moderna. They found that those who’d never been infected by SARS-CoV-2 developed antibodies at low levels within 9 to 12 days of receiving their first dose of vaccine.
But in 41 people who tested positive for SARS-CoV-2 antibodies prior to getting the first shot, the immune response looked strikingly different. They generated high levels of antibodies within just a few days of getting the vaccine. Compared across different time intervals, previously infected people had immune responses 10 to 20 times that observed in uninfected people. Following their second vaccine dose, it was roughly the same story. Antibody levels in those with a prior infection were about 10 times greater than the others.
Both vaccines were generally well tolerated. But, because their immune systems were already in high gear, people who were previously infected tended to have more symptoms following their first shot, such as pain and swelling at the injection site. They also were more likely to report other less common symptoms, including fatigue, fever, chills, headache, muscle aches, and joint pain.
Though sometimes it may not seem like it, COVID-19 and the mRNA vaccines are still relatively new. Researchers haven’t yet been able to study how long these vaccines confer immunity to the disease, which has now claimed the lives of more than 500,000 Americans. But these findings do suggest that a single dose of the Pfizer or Moderna vaccines can produce a rapid and strong immune response in people who’ve already recovered from COVID-19.
If other studies support these results, the U.S. Food and Drug Administration (FDA) might decide to consider whether one dose is enough for people who’ve had a prior COVID-19 infection. Such a policy is already under consideration in France and, if implemented, would help to extend vaccine supply and get more people vaccinated sooner. But any serious consideration of this option will require more data. It will also be up to the expert advisors at FDA and Centers for Disease Control and Prevention (CDC) to decide.
For now, the most important thing all of us can all do to get this terrible pandemic under control is to follow the 3 W’s—wear our masks, wash our hands, watch our distance from others—and roll up our sleeves for the vaccine as soon as it’s available to us.
 Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine. Krammer F et al. medRxiv. 2021 Feb 1.
COVID-19 Research (NIH)
Krammer Lab (Icahn School of Medicine at Mount Sinai, New York, NY)
Simon Lab (Icahn School of Medicine at Mount Sinai)
NIH Support: National Institute of Allergy and Infectious Diseases
Posted on by Dr. Francis Collins
It’s truly encouraging to witness people all across our nation rolling up their sleeves to get their COVID-19 vaccines. That is our best chance to end this pandemic. But this is the third coronavirus to emerge and cause serious human illness in the last 20 years, and it’s probably not the last. So, this is also an opportunity to step up our efforts to develop vaccines to combat future strains of disease-causing coronavirus. With this in mind, I’m heartened by a new NIH-funded study showing the potential of a remarkably adaptable, nanoparticle-based approach to coronavirus vaccine development .
Both COVID-19 vaccines currently authorized for human use by the Food and Drug Administration (FDA) work by using mRNA to instruct our cells to make an essential portion of the spike protein of SARS-CoV-2, which is the novel coronavirus that causes COVID-19. As our immune system learns to recognize this protein fragment as foreign, it produces antibodies to attack SARS-CoV-2 and prevent COVID-19. What makes the new vaccine technology so powerful is that it raises the possibility of training the immune system to recognize not just one strain of coronavirus—but up to eight—with a single shot.
This approach has not yet been tested in people, but when a research team, led by Pamela Bjorkman, California Institute of Technology, Pasadena, injected this new type of vaccine into mice, it spurred the production of antibodies that react to a variety of different coronaviruses. In fact, some of the mouse antibodies proved to be reactive to related strains of coronavirus that weren’t even represented in the vaccine. These findings suggest that if presented with multiple different fragments of the spike protein’s receptor binding domain (RBD), which is what SARS-like coronaviruses use to infect human cells, the immune system may learn to recognize common features that might protect against as-yet unknown, newly emerging coronaviruses.
This new work, published in the journal Science, utilizes a technology called a mosaic nanoparticle vaccine platform . Originally developed by collaborators at the University of Oxford, United Kingdom, the nanoparticle component of the platform is a “cage” made up of 60 identical proteins. Each of those proteins has a small protein tag that functions much like a piece of Velcro®. In their SARS-CoV-2 work, Bjorkman and her colleagues, including graduate student Alex A. Cohen, engineered multiple different fragments of the spike protein so each had its own Velcro-like tag. When mixed with the nanoparticle, the spike protein fragments stuck to the cage, resulting in a vaccine nanoparticle with spikes representing four to eight distinct coronavirus strains on its surface. In this instance, the researchers chose spike protein fragments from several different strains of SARS-CoV-2, as well as from other related bat coronaviruses thought to pose a threat to humans.
The researchers then injected the vaccine nanoparticles into mice and the results were encouraging. After inoculation, the mice began producing antibodies that could neutralize many different strains of coronavirus. In fact, while more study is needed to understand the mechanisms, the antibodies responded to coronavirus strains that weren’t even represented on the mosaic nanoparticle. Importantly, this broad antibody response came without apparent loss in the antibodies’ ability to respond to any one particular coronavirus strain.
The findings raise the exciting possibility that this new vaccine technology could provide protection against many coronavirus strains with a single shot. Of course, far more study is needed to explore how well such vaccines work to protect animals against infection, and whether they will prove to be safe and effective in people. There will also be significant challenges in scaling up manufacturing. Our goal is not to replace the mRNA COVID-19 vaccines that scientists developed at such a remarkable pace over the last year, but to provide much-needed vaccine strategies and tools to respond swiftly to the emerging coronavirus strains of the future.
As we double down on efforts to combat COVID-19, we must also come to grips with the fact that SARS-CoV-2 isn’t the first—and surely won’t be the last—novel coronavirus to cause disease in humans. With continued research and development of new technologies such as this one, the hope is that we will come out of this terrible pandemic better prepared for future infectious disease threats.
 Mosaic RBD nanoparticles elicit neutralizing antibodies against SARS-CoV-2 and zoonotic coronaviruses. Cohen AA, Gnanapragasam PNP, Lee YE, Hoffman PR, Ou S, Kakutani LM, Keeffe JR, Barnes CO, Nussenzweig MC, Bjorkman PJ. Science. 2021 Jan 12.
COVID-19 Research (NIH)
Bjorkman Lab (California Institute of Technology, Pasadena)
NIH Support: National Institute of Allergy and Infectious Diseases
Posted on by Dr. Francis Collins
It’s 2021—Happy New Year! Time sure flies in the blogosphere. It seems like just yesterday that I started the NIH Director’s Blog to highlight recent advances in biology and medicine, many supported by NIH. Yet it turns out that more than eight years have passed since this blog got rolling and we are fast approaching my 1,000th post!
I’m pleased that millions of you have clicked on these posts to check out some very cool science and learn more about NIH and its mission. Thanks to the wonders of social media software, we’ve been able to tally up those views to determine each year’s most-popular post. So, I thought it would be fun to ring in the New Year by looking back at a few of your favorites, sort of a geeky version of a top 10 countdown or the People’s Choice Awards. It was interesting to see what topics generated the greatest interest. Spoiler alert: diet and exercise seemed to matter a lot! So, without further ado, I present the winners:
2013: Fighting Obesity: New Hopes from Brown Fat. Brown fat, one of several types of fat made by our bodies, was long thought to produce body heat rather than store energy. But Shingo Kajimura and his team at the University of California, San Francisco, showed in a study published in the journal Nature, that brown fat does more than that. They discovered a gene that acts as a molecular switch to produce brown fat, then linked mutations in this gene to obesity in humans.
What was also nice about this blog post is that it appeared just after Kajimura had started his own lab. In fact, this was one of the lab’s first publications. One of my goals when starting the blog was to feature young researchers, and this work certainly deserved the attention it got from blog readers. Since highlighting this work, research on brown fat has continued to progress, with new evidence in humans suggesting that brown fat is an effective target to improve glucose homeostasis.
2014: In Memory of Sam Berns. I wrote this blog post as a tribute to someone who will always be very near and dear to me. Sam Berns was born with Hutchinson-Gilford progeria syndrome, one of the rarest of rare diseases. After receiving the sad news that this brave young man had passed away, I wrote: “Sam may have only lived 17 years, but in his short life he taught the rest of us a lot about how to live.”
Affecting approximately 400 people worldwide, progeria causes premature aging. Without treatment, children with progeria, who have completely normal intellectual development, die of atherosclerotic cardiovascular disease, on average in their early teens.
From interactions with Sam and his parents in the early 2000s, I started to study progeria in my NIH lab, eventually identifying the gene responsible for the disorder. My group and others have learned a lot since then. So, it was heartening last November when the Food and Drug Administration approved the first treatment for progeria. It’s an oral medication called Zokinvy (lonafarnib) that helps prevent the buildup of defective protein that has deadly consequences. In clinical trials, the drug increased the average survival time of those with progeria by more than two years. It’s a good beginning, but we have much more work to do in the memory of Sam and to help others with progeria. Watch for more about new developments in applying gene editing to progeria in the next few days.
2015: Cytotoxic T Cells on Patrol. Readers absolutely loved this post. When the American Society of Cell Biology held its first annual video competition, called CellDance, my blog featured some of the winners. Among them was this captivating video from Alex Ritter, then working with cell biologist Jennifer Lippincott-Schwartz of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development. The video stars a roving, specialized component of our immune system called cytotoxic T cells. Their job is to seek out and destroy any foreign or detrimental cells. Here, these T cells literally convince a problem cell to commit suicide, a process that takes about 10 minutes from detection to death.
These cytotoxic T cells are critical players in cancer immunotherapy, in which a patient’s own immune system is enlisted to control and, in some cases, even cure the cancer. Cancer immunotherapy remains a promising area of research that continues to progress, with a lot of attention now being focused on developing immunotherapies for common, solid tumors like breast cancer. Ritter is currently completing a postdoctoral fellowship in the laboratory of Ira Mellman, Genentech, South San Francisco. His focus has shifted to how cancer cells protect themselves from T cells. And video buffs—get this—Ritter says he’s now created even cooler videos that than the one in this post.
2016: Exercise Releases Brain-Healthy Protein. The research literature is pretty clear: exercise is good for the brain. In this very popular post, researchers led by Hyo Youl Moon and Henriette van Praag of NIH’s National Institute on Aging identified a protein secreted by skeletal muscle cells to help explore the muscle-brain connection. In a study in Cell Metabolism, Moon and his team showed that this protein called cathepsin B makes its way into the brain and after a good workout influences the development of new neural connections. This post is also memorable to me for the photo collage that accompanied the original post. Why? If you look closely at the bottom right, you’ll see me exercising—part of my regular morning routine!
2017: Muscle Enzyme Explains Weight Gain in Middle Age. The struggle to maintain a healthy weight is a lifelong challenge for many of us. While several risk factors for weight gain, such as counting calories, are within our control, there’s a major one that isn’t: age. Jay Chung, a researcher with NIH’s National Heart, Lung, and Blood Institute, and his team discovered that the normal aging process causes levels of an enzyme called DNA-PK to rise in animals as they approach middle age. While the enzyme is known for its role in DNA repair, their studies showed it also slows down metabolism, making it more difficult to burn fat.
Since publishing this paper in Cell Metabolism, Chung has been busy trying to understand how aging increases the activity of DNA-PK and its ability to suppress renewal of the cell’s energy-producing mitochondria. Without renewal of damaged mitochondria, excess oxidants accumulate in cells that then activate DNA-PK, which contributed to the damage in the first place. Chung calls it a “vicious cycle” of aging and one that we’ll be learning more about in the future.
2018: Has an Alternative to Table Sugar Contributed to the C. Diff. Epidemic? This impressive bit of microbial detective work had blog readers clicking and commenting for several weeks. So, it’s no surprise that it was the runaway People’s Choice of 2018.
Clostridium difficile (C. diff) is a common bacterium that lives harmlessly in the gut of most people. But taking antibiotics can upset the normal balance of healthy gut microbes, allowing C. diff. to multiply and produce toxins that cause inflammation and diarrhea.
In the 2000s, C. diff. infections became far more serious and common in American hospitals, and Robert Britton, a researcher at Baylor College of Medicine, Houston, wanted to know why. He and his team discovered that two subtypes of C. diff have adapted to feed on the sugar trehalose, which was approved as a food additive in the United States during the early 2000s. The team’s findings, published in the journal Nature, suggested that hospitals and nursing homes battling C. diff. outbreaks may want to take a closer look at the effect of trehalose in the diet of their patients.
2019: Study Finds No Benefit for Dietary Supplements. This post that was another one that sparked a firestorm of comments from readers. A team of NIH-supported researchers, led by Fang Fang Zhang, Tufts University, Boston, found that people who reported taking dietary supplements had about the same risk of dying as those who got their nutrients through food. What’s more, the mortality benefits associated with adequate intake of vitamin A, vitamin K, magnesium, zinc, and copper were limited to amounts that are available from food consumption. The researchers based their conclusion on an analysis of the well-known National Health and Nutrition Examination Survey (NHANES) between 1999-2000 and 2009-2010 survey data. The team, which reported its data in the Annals of Internal Medicine, also uncovered some evidence suggesting that certain supplements might even be harmful to health when taken in excess.
2020: Genes, Blood Type Tied to Risk of Severe COVID-19. Typically, my blog focuses on research involving many different diseases. That changed in 2020 due to the emergence of a formidable public health challenge: the coronavirus disease 2019 (COVID-19) pandemic. Since last March, the blog has featured 85 posts on COVID-19, covering all aspects of the research response and attracting more visitors than ever. And which post got the most views? It was one that highlighted a study, published last June in the New England Journal of Medicine, that suggested the clues to people’s variable responses to COVID-19 may be found in our genes and our blood types.
The researchers found that gene variants in two regions of the human genome are associated with severe COVID-19 and correspondingly carry a greater risk of COVID-19-related death. The two stretches of DNA implicated as harboring risks for severe COVID-19 are known to carry some intriguing genes, including one that determines blood type and others that play various roles in the immune system.
In fact, the findings suggest that people with blood type A face a 50 percent greater risk of needing oxygen support or a ventilator should they become infected with the novel coronavirus. In contrast, people with blood type O appear to have about a 50 percent reduced risk of severe COVID-19.
That’s it for the blog’s year-by-year Top Hits. But wait! I’d also like to give shout outs to the People’s Choice winners in two other important categories—history and cool science images.
Top History Post: HeLa Cells: A New Chapter in An Enduring Story. Published in August 2013, this post remains one of the blog’s greatest hits with readers. The post highlights science’s use of cancer cells taken in the 1950s from a young Black woman named Henrietta Lacks. These “HeLa” cells had an amazing property not seen before: they could be grown continuously in laboratory conditions. The “new chapter” featured in this post is an agreement with the Lacks family that gives researchers access to the HeLa genome data, while still protecting the family’s privacy and recognizing their enormous contribution to medical research. And the acknowledgments rightfully keep coming from those who know this remarkable story, which has been chronicled in both book and film. Recently, the U.S. Senate and House of Representatives passed the Henrietta Lacks Enhancing Cancer Research Act to honor her extraordinary life and examine access to government-funded cancer clinical trials for traditionally underrepresented groups.
Top Snapshots of Life: A Close-up of COVID-19 in Lung Cells. My blog posts come in several categories. One that you may have noticed is “Snapshots of Life,” which provides a showcase for cool images that appear in scientific journals and often dominate Science as Art contests. My blog has published dozens of these eye-catching images, representing a broad spectrum of the biomedical sciences. But the blog People’s Choice goes to a very recent addition that reveals exactly what happens to cells in the human airway when they are infected with the coronavirus responsible for COVID-19. This vivid image, published in the New England Journal of Medicine, comes from the lab of pediatric pulmonologist Camille Ehre, University of North Carolina at Chapel Hill. This image squeezed in just ahead of another highly popular post from Steve Ramirez, Boston University, in 2019 that showed “What a Memory Looks Like.”
As we look ahead to 2021, I want to thank each of my blog’s readers for your views and comments over the last eight years. I love to hear from you, so keep on clicking! I’m confident that 2021 will generate a lot more amazing and bloggable science, including even more progress toward ending the COVID-19 pandemic that made our past year so very challenging.
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.
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)