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A Real-World Look at COVID-19 Vaccines Versus New Variants

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A woman receiving a vaccine from a doctor
Credit: Getty Images/Andrey Popov

Clinical trials have shown the COVID-19 vaccines now being administered around the country are highly effective in protecting fully vaccinated individuals from the coronavirus SARS-CoV-2. But will they continue to offer sufficient protection as the frequency of more transmissible and, in some cases, deadly emerging variants rise?

More study and time is needed to fully answer this question. But new data from Israel offers an early look at how the Pfizer/BioNTech vaccine is holding up in the real world against coronavirus “variants of concern,” including the B.1.1.7 “U.K. variant” and the B.1.351 “South African variant.” And, while there is some evidence of breakthrough infections, the findings overall are encouraging.

Israel was an obvious place to look for answers to breakthrough infections. By last March, more than 80 percent of the country’s vaccine-eligible population had received at least one dose of the Pfizer/BioNTech vaccine. An earlier study in Israel showed that the vaccine offered 94 percent to 96 percent protection against infection across age groups, comparable to the results of clinical trials. But it didn’t dig into any important differences in infection rates with newly emerging variants, post-vaccination.

To dig a little deeper into this possibility, a team led by Adi Stern, Tel Aviv University, and Shay Ben-Shachar, Clalit Research Institute, Tel Aviv, looked for evidence of breakthrough infections in several hundred people who’d had at least one dose of the Pfizer/BioNTech vaccine [1]. The idea was, if this vaccine were less effective in protecting against new variants of concern, the proportion of infections caused by them should be higher in vaccinated compared to unvaccinated individuals.

During the study, reported as a pre-print in MedRxiv, it became clear that B.1.1.7 was the predominant SARS-CoV-2 variant in Israel, with its frequency increasing over time. By comparison, the B.1.351 “South African” variant was rare, accounting for less than 1 percent of cases sampled in the study. No other variants of concern, as defined by the World Health Organization, were detected.

Graph showing percentages of virus variants. B.1.1.7 is nearly 100% by March
Caption: Changing variant frequencies during the study. Credit: Adapted from Kustin T, medRxiv, 2021

In total, the researchers sequenced SARS-CoV-2 from more than 800 samples, including vaccinated individuals and matched unvaccinated individuals with similar characteristics including age, sex, and geographic location. They identified nearly 250 instances in which an individual became infected with SARS-CoV-2 after receiving their first vaccine dose, meaning that they were only partially protected. Almost 150 got infected sometime after receiving the second dose.

Interestingly, the evidence showed that these breakthrough infections with the B.1.1.7 variant occurred slightly more often in people after the first vaccine dose compared to unvaccinated people. No evidence was found for increased breakthrough rates of B.1.1.7 a week or more after the second dose. In contrast, after the second vaccine dose, infection with the B.1.351 became slightly more frequent. The findings show that people remain susceptible to B.1.1.7 following a single dose of vaccine. They also suggest that the two-dose vaccine may be slightly less effective against B.1.351 compared to the original or B.1.1.7 variants.

It’s important to note, however, that the researchers only observed 11 infections with the B.1.351 variant—eight of them in individuals vaccinated with two doses. Interestingly, all eight tested positive seven to 13 days after receiving their second dose. No one in the study tested positive for this variant two weeks or more after the second dose.

Many questions remain, including whether the vaccines reduced the duration and/or severity of infections. Nevertheless, the findings are a reminder that—while these vaccines offer remarkable protection—they are not foolproof. Breakthrough infections can and do occur.

In fact, in a recent report in the New England Journal of Medicine, NIH-supported researchers detailed the experiences of two fully vaccinated individuals in New York who tested positive for COVID-19 [2]. Though both recovered quickly at home, genomic data in those cases revealed multiple mutations in both viral samples, including a variant first identified in South Africa and Brazil, and another, which has been spreading in New York since November.

These findings in Israel and the United States also highlight the importance of tracking coronavirus variants and making sure that all eligible individuals get fully vaccinated as soon as they have the opportunity. They show that COVID-19 testing will continue to play an important role, even in those who’ve already been vaccinated. This is even more important now as new variants continue to rise in frequency.

Just over 100 million Americans aged 18 and older—about 40 percent of adults—are now fully vaccinated [3]. However, we need to get that number much higher. If you or a loved one haven’t yet been vaccinated, please consider doing so. It will help to save lives and bring this pandemic to an end.

References:

[1] Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2 mRNA vaccinated individuals. Kustin T et al. medRxiv. April 16, 2021.

[2] Vaccine breakthrough infections with SARS-CoV-2 variants. Hacisuleyman E, Hale C, Saito Y, Blachere NE, Bergh M, Conlon EG, Schaefer-Babajew DJ, DaSilva J, Muecksch F, Gaebler C, Lifton R, Nussenzweig MC, Hatziioannou T, Bieniasz PD, Darnell RB. N Engl J Med. 2021 Apr 21.

[3] COVID-19 vaccinations in the United States. Centers for Disease Control and Prevention.

Links:

COVID-19 Research (NIH)

Stern Lab (Tel Aviv University, Israel)

Ben-Shachar Lab (Clalit Research Institute, Tel Aviv, Israel)

NIH Support: National Institute of Allergy and Infectious Diseases


Israeli Study Offers First Real-World Glimpse of COVID-19 Vaccines in Action

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COVID-19 Update: Large scale clinical trial
Credit: Getty Images/Hispanolistic

There are many reasons to be excited about the three COVID-19 vaccines that are now getting into arms across the United States. At the top of the list is their extremely high level of safety and protection against SARS-CoV-2, the coronavirus that causes COVID-19. Of course, those data come from clinical trials that were rigorously conducted under optimal research conditions. One might wonder how well those impressive clinical trial results will translate to the real world.

A new study published in the New England Journal of Medicine [1] offers an early answer for the Pfizer/BioNTech vaccine. The Pfizer product is an mRNA vaccine that was found in a large clinical trial to be up to 95 percent effective in preventing COVID-19, leading to its Emergency Use Authorization last December.

The new data, which come from Israel, are really encouraging. Based on a detailed analysis of nearly 600,000 people vaccinated in that nation, a research team led by Ran Balicer, The Clalit Research Institute, Tel Aviv, found that the risk of symptomatic COVID-19 infection dropped by 94 percent a week after individuals had received both doses of the Pfizer vaccine. That’s essentially the same very high level of protection that was seen in the data gathered in the earlier U.S. clinical trial.

The study also found that just a single shot of the two-dose vaccine led to a 57 percent drop in the incidence of symptomatic COVID-19 infections and a 62 percent decline in the risk of severe illness after two to three weeks. Note, however, that the protection clearly got better after folks received the second dose. While it’s too soon to say how many lives were saved in Israel thanks to full vaccination, the early data not surprisingly suggest a substantial reduction in mortality.

Israel, which is about as large as New Jersey with a population of around 9 million, currently has the world’s highest COVID-19 vaccination rate. In addition to its relatively small size, Israel also has a national health system and one of the world’s largest integrated health record databases, making it a natural choice to see how well one of the new vaccines was working in the real world.

The study took place from December 20, 2020, the start of Israel’s first vaccination drive, through February 1, 2021. This also coincided with Israel’s third and largest wave of COVID-19 infections and illness. During this same period, the B.1.1.7 variant, which was first detected in the United Kingdom, gradually became Israel’s dominant strain. That’s notable because the U.K. variant spreads from person-to-person more readily and may be associated with an increased risk of death compared with other variants [2].

Balicer and his colleagues reviewed data on 596,618 fully vaccinated individuals, ages 16 and older. A little less than one third—about 170,000—of the people studied were over age 60. To see how well the vaccine worked, the researchers carefully matched each of the vaccinated individuals in the study to an unvaccinated person with similar demographics as well as risks of infection, severe illness, and other important health attributes.

The results showed that the vaccine works remarkably well. In fact, the researchers determined that the Pfizer/BioNTech vaccine is similarly effective—94 percent to 96 percent—across adults in different age groups. It also appears that the vaccine works about equally well for individuals age 70 and older as it does for younger people.

So far, more than 92 million total vaccine doses have been administered in the U.S. With the Janssen COVID-19 vaccine (also called the Johnson & Johnson vaccine) now coming online, that number will rise even faster. For those of you who haven’t had the opportunity just yet, these latest findings should come as added encouragement to roll up your sleeve for any one of the authorized vaccines as soon as your invitation arrives.

References:

[1] BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. Dagan N, Barda N, Kepten E, Miron O, Perchik S, Katz MA, Hernán MA, Lipsitch M, Reis B, Balicer RD. N Engl J Med. 2021 Feb 24.

[2] Emerging SARS-CoV-2 Variants. Centers for Disease Control and Prevention.

Links:

COVID-19 Research (NIH)

Clalit Research Institute (Tel Aviv, Israel)

Ran Balicer (Clalit Research Institute)


Is One Vaccine Dose Enough After COVID-19 Infection?

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COVID-19 vaccination record card
Credit: iStock/Bill Oxford

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


Following COVID-19 Vaccines Across the United States

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Vaccine Tracker

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)



What A Year It Was for Science Advances!

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Science Breakthroughs of the Year 2020

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)


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