Moderna
How COVID-19 Immunity Holds Up Over Time
Posted on by Lawrence Tabak, D.D.S., Ph.D.

More than 215 million people in the United States are now fully vaccinated against the SARS-CoV-2 virus responsible for COVID-19 [1]. More than 40 percent—more than 94 million people—also have rolled up their sleeves for an additional, booster dose. Now, an NIH-funded study exploring how mRNA vaccines are performing over time comes as a reminder of just how important it will be to keep those COVID-19 vaccines up to date as coronavirus variants continue to circulate.
The results, published in the journal Science Translational Medicine, show that people who received two doses of either the Pfizer or Moderna COVID-19 mRNA vaccines did generate needed virus-neutralizing antibodies [2]. But levels of those antibodies dropped considerably after six months, suggesting declining immunity over time.
The data also reveal that study participants had much reduced protection against newer SARS-CoV-2 variants, including Delta and Omicron. While antibody protection remained stronger in people who’d also had a breakthrough infection, even that didn’t appear to offer much protection against infection by the Omicron variant.
The new study comes from a team led by Shan-Lu Liu at The Ohio State University, Columbus. They wanted to explore how well vaccine-acquired immune protection holds up over time, especially in light of newly arising SARS-CoV-2 variants.
This is an important issue going forward because mRNA vaccines train the immune system to produce antibodies against the spike proteins that crown the surface of the SARS-CoV-2 coronavirus. These new variants often have mutated, or slightly changed, spike proteins compared to the original one the immune system has been trained to detect, potentially dampening the immune response.
In the study, the team collected serum samples from 48 fully vaccinated health care workers at four key time points: 1) before vaccination, 2) three weeks after the first dose, 3) one month after the second dose, and 4) six months after the second dose.
They then tested the ability of antibodies in those samples to neutralize spike proteins as a correlate for how well a vaccine works to prevent infection. The spike proteins represented five major SARS-CoV-2 variants. The variants included D614G, which arose very soon after the coronavirus first was identified in Wuhan and quickly took over, as well as Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529).
The researchers explored in the lab how neutralizing antibodies within those serum samples reacted to SARS-CoV-2 pseudoviruses representing each of the five variants. SARS-CoV-2 pseudoviruses are harmless viruses engineered, in this case, to bear coronavirus spike proteins on their surfaces. Because they don’t replicate, they are safe to study without specially designed biosafety facilities.
At any of the four time points, antibodies showed a minimal ability to neutralize the Omicron spike protein, which harbors about 30 mutations. These findings are consistent with an earlier study showing a significant decline in neutralizing antibodies against Omicron in people who’ve received the initial series of two shots, with improved neutralizing ability following an additional booster dose.
The neutralizing ability of antibodies against all other spike variants showed a dramatic decline from 1 to 6 months after the second dose. While there was a marked decline over time after both vaccines, samples from health care workers who’d received the Moderna vaccine showed about twice the neutralizing ability of those who’d received the Pfizer vaccine. The data also suggests greater immune protection in fully vaccinated healthcare workers who’d had a breakthrough infection with SARS-CoV-2.
In addition to recommending full vaccination for all eligible individuals, the Centers for Disease Control and Prevention (CDC) now recommends everyone 12 years and up should get a booster dose of either the Pfizer or Moderna vaccines at least five months after completing the primary series of two shots [3]. Those who’ve received the Johnson & Johnson vaccine should get a booster at least two months after receiving the initial dose.
While plenty of questions about the durability of COVID-19 immunity over time remain, it’s clear that the rapid deployment of multiple vaccines over the course of this pandemic already has saved many lives and kept many more people out of the hospital. As the Omicron threat subsides and we start to look forward to better days ahead, it will remain critical for researchers and policymakers to continually evaluate and revise vaccination strategies and recommendations, to keep our defenses up as this virus continues to evolve.
References:
[1] COVID-19 vaccinations in the United States. Centers for Disease Control and Prevention. February 27, 2022.
[2] Neutralizing antibody responses elicited by SARS-CoV-2 mRNA vaccination wane over time and are boosted by breakthrough infection. Evans JP, Zeng C, Carlin C, Lozanski G, Saif LJ, Oltz EM, Gumina RJ, Liu SL. Sci Transl Med. 2022 Feb 15:eabn8057.
[3] COVID-19 vaccine booster shots. Centers for Disease Control and Prevention. Feb 2, 2022.
Links:
COVID-19 Research (NIH)
Shan-Lu Liu (The Ohio State University, Columbus)
NIH Support: National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development
Time for My Booster Shot
Posted on by Dr. Francis Collins

Is One Vaccine Dose Enough After COVID-19 Infection?
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 [1]. 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.
Reference:
[1] 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.
Links:
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
A Double Thumbs Up
Posted on by Dr. Francis Collins

Following COVID-19 Vaccines Across the United States
Posted on by Dr. Francis Collins

Recently, there is a new and very hopeful COVID-19 number for everyone to track: the total number of vaccine doses that have been administered in the United States. If 80 percent of Americans roll up their sleeves in the coming months and accept COVID-19 vaccinations, we can greatly slow the spread of the novel coronavirus in our communities and bring this horrible pandemic to an end in 2021.
So far, more than 20 million people in our country have received one or two doses of either the Pfizer or Moderna vaccine. While this number is lower than initially projected for a variety of logistical reasons, we’re already seeing improvements in the distribution system that has made it possible to get close to 1 million doses administered per day.
If you want to keep track of the vaccine progress in your state over the coming weeks, it’s now pretty easy to do online. A fine resource is the vaccine information on the Centers for Disease Control and Prevention (CDC) COVID Data Tracker. It offers an interactive state-by-state map, as well as data on vaccinations in long-term care facilities. Keep in mind that there’s a delay of three to five days in reporting actual vaccinations from the states.
There’s also a lot of useful information on the Johns Hopkins Coronavirus Resource Center’s Vaccine Tracker. Posting the daily updates is a team, led by William Moss, that draws on the expertise of data scientists, analysts, programmers, and researchers. The Hopkins team gathers its vaccination data from each state’s official dashboard, webpages, press releases, or wherever cumulative numbers are reported. Not all states publish the same vaccine information, and that’s what can make the Vaccine Tracker so challenging to compile.
The Hopkins team now presents on its homepage the top 10 U. S. states and territories to vaccinate fully the highest percentage of their residents. With another click, there’s also a full rundown of vaccine administration by state and territory, plus the District of Columbia. The site also links to lots of other information about COVID-19—including cases, testing, contact tracing, and an interactive tool about vaccine development.
In uncertain times, knowledge can be a source of comfort. That’s what makes these interactive COVID-19 resources so helpful and empowering. They show that, with time, safe and effective COVID-19 vaccines will indeed coming to everyone. I hope that you will accept your vaccine, like I did when given the opportunity. However, until we get to the point where most Americans are immunized, we must stay vigilant and keep up our tried-and-true public health measures such as wearing masks, limiting physical interactions (especially indoors), and washing our hands.
Links:
COVID-19 Research (NIH)
CDC COVID Data Tracker (Centers for Disease Control and Prevention, Atlanta)
Coronavirus Resource Center (Johns Hopkins University School of Medicine)
William Moss (Johns Hopkins University, Baltimore)
International Vaccine Access Center (Johns Hopkins Bloomberg School of Public Health, Baltimore)
Getting My COVID-19 Booster Shot
Posted on by Dr. Francis Collins

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)
Accepting the COVID-19 Vaccine
Posted on by Dr. Francis Collins

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