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How COVID-19 Immunity Holds Up Over Time

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Antibody protection. Graph showing gradient of many antibodies early and less as time goes on

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.


[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.


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

‘Decoy’ Protein Works Against Multiple Coronavirus Variants in Early Study

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Virus's spikes being covered with ACE2 decoys. ACE2 receptors on surface are empty

The NIH continues to support the development of some very innovative therapies to control SARS-CoV-2, the coronavirus that causes COVID-19. One innovative idea involves a molecular decoy to thwart the coronavirus.

How’s that? The decoy is a specially engineered protein particle that mimics the 3D structure of the ACE2 receptor, a protein on the surface of our cells that the virus’s spike proteins bind to as the first step in causing an infection.

The idea is when these ACE2 decoys are administered therapeutically, they will stick to the spike proteins that crown the coronavirus (see image above). With its spikes covered tightly in decoy, SARS-CoV-2 has a more-limited ability to attach to the real ACE2 and infect our cells.

Recently, the researchers published their initial results in the journal Nature Chemical Biology, and the early data look promising [1]. They found in mouse models of severe COVID-19 that intravenous infusion of an engineered ACE2 decoy prevented lung damage and death. Though more study is needed, the researchers say the decoy therapy could potentially be delivered directly to the lungs through an inhaler and used alone or in combination with other COVID-19 treatments.

The findings come from a research team at the University of Illinois Chicago team, led by Asrar Malik and Jalees Rehman, working in close collaboration with their colleagues at the University of Illinois Urbana-Champaign. The researchers had been intrigued by an earlier clinical trial testing the ACE2 decoy strategy [2]. However, in this earlier attempt, the clinical trial found no reduction in mortality. The ACE2 drug candidate, which is soluble and degrades in the body, also proved ineffective in neutralizing the virus.

Rather than give up on the idea, the UIC team decided to give it a try. They engineered a new soluble version of ACE2 that structurally might work better as a decoy than the original one. Their version of ACE2, which includes three changes in the protein’s amino acid building blocks, binds the SARS-CoV-2 spike protein much more tightly. In the lab, it also appeared to neutralize the virus as well as monoclonal antibodies used to treat COVID-19.

To put it to the test, they conducted studies in mice. Normal mice don’t get sick from SARS-CoV-2 because the viral spike can’t bind well to the mouse version of the ACE2 receptor. So, the researchers did their studies in a mouse that carries the human ACE2 and develops a severe acute respiratory syndrome somewhat similar to that seen in humans with severe COVID-19.

In their studies, using both the original viral isolate from Washington State and the Gamma variant (P.1) first detected in Brazil, they found that infected mice infused with their therapeutic ACE2 protein had much lower mortality and showed few signs of severe acute respiratory syndrome. While the protein worked against both versions of the virus, infection with the more aggressive Gamma variant required earlier treatment. The treated mice also regained their appetite and weight, suggesting that they were making a recovery.

Further studies showed that the decoy bound to spike proteins from every variant tested, including Alpha, Beta, Delta and Epsilon. (Omicron wasn’t yet available at the time of the study.) In fact, the decoy bound just as well, if not better, to new variants compared to the original virus.

The researchers will continue their preclinical work. If all goes well, they hope to move their ACE2 decoy into a clinical trial. What’s especially promising about this approach is it could be used in combination with treatments that work in other ways, such as by preventing virus that’s already infected cells from growing or limiting an excessive and damaging immune response to the infection.

Last week, more than 17,500 people in the United States were hospitalized with severe COVID-19. We’ve got to continue to do all we can to save lives, and it will take lots of innovative ideas, like this ACE2 decoy, to put us in a better position to beat this virus once and for all.


[1] Engineered ACE2 decoy mitigates lung injury and death induced by SARS-CoV-2 variants.
Zhang L, Dutta S, Xiong S, Chan M, Chan KK, Fan TM, Bailey KL, Lindeblad M, Cooper LM, Rong L, Gugliuzza AF, Shukla D, Procko E, Rehman J, Malik AB. Nat Chem Biol. 2022 Jan 19.

[2] Recombinant human angiotensin-converting enzyme 2 (rhACE2) as a treatment for patients with COVID-19 (APN01-COVID-19).


COVID-19 Research (NIH)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (NIH)

Asrar Malik (University of Illinois Chicago)

Jalees Rehman (University of Illinois Chicago)

NIH Support: National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases

How One Change to The Coronavirus Spike Influences Infectivity

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electron micrograph of COVID-19 viruses
Caption: Spike proteins (blue) crown SARS-CoV-2, the virus that causes COVID-19. Once the virus enters humans, the spike protein is decorated with sugars that attach to some of its amino acids, forming O-glycans. Loss of key O-glycans may facilitate viral spread to human cells. Credit: National Institute of Allergy and Infectious Diseases, NIH

Since joining NIH, I’ve held a number of different leadership positions. But there is one position that thankfully has remained constant for me: lab chief. I run my own research laboratory at NIH’s National Institute of Dental and Craniofacial Research (NIDCR).

My lab studies a biochemical process called O-glycosylation. It’s fundamental to life and fascinating to study. Our cells are often adorned with a variety of carbohydrate sugars. O-glycosylation refers to the biochemical process through which these sugar molecules, either found at the cell surface or secreted, get added to proteins. The presence or absence of these sugars on certain proteins plays fundamental roles in normal tissue development and first-line human immunity. It also is associated with various diseases, including cancer.

Our lab recently joined a team of NIH scientists led by my NIDCR colleague Kelly Ten Hagen to demonstrate how O-glycosylation can influence SARS-CoV-2, the coronavirus that causes COVID-19, and its ability to fuse to cells, which is a key step in infecting them. In fact, our data, published in the journal Proceedings of the National Academy of Sciences, indicate that some variants, seem to have mutated to exploit the process to their advantage [1].

The work builds on the virus’s reliance on the spike proteins that crown its outer surface to attach to human cells. Once there, the spike protein must be activated to fuse and launch an infection. That happens when enzymes produced by our own cells make a series of cuts, or cleavages, to the spike protein.

The first cut comes from an enzyme called furin. We and others had earlier evidence that O-glycosylation can affect the way furin makes those cuts. That got us thinking: Could O-glycosylation influence the interaction between furin and the spike protein? The furin cleavage area of the viral spike was indeed adorned with sugars, and their presence or absence might influence spike activation by furin.

We also noticed the Alpha and Delta variants carry a mutation that removes the amino acid proline in a specific spot. That was intriguing because we knew from earlier work that enzymes called GALNTs, which are responsible for adding bulky sugar molecules to proteins, prefer prolines near O-glycosylation sites.

It also suggested that loss of proline in the new variants could mean decreased O-glycosylation, which might then influence the degree of furin cleavage and SARS-CoV-2’s ability to enter cells. I should note that the recent Omicron variant was not examined in the current study.

After detailed studies in fruit fly and mammalian cells, we demonstrated in the original SARS-CoV-2 virus that O-glycosylation of the spike protein decreases furin cleavage. Further experiments then showed that the GALNT1 enzyme adds sugars to the spike protein and this addition limits the ability of furin to make the needed cuts and activate the spike protein.

Importantly, the spike protein change found in the Alpha and Delta variants lowers GALNT1 activity, making it easier for furin to start its activating cuts. It suggests that glycosylation of the viral spike by GALNT1 may limit infection with the original virus, and that the Alpha and Delta variant mutation at least partially overcomes this effect, to potentially make the virus more infectious.

Building on these studies, our teams looked for evidence of GALNT1 in the respiratory tracts of healthy human volunteers. We found that the enzyme is indeed abundantly expressed in those cells. Interestingly, those same cells also express the ACE2 receptor, which SARS-CoV-2 depends on to infect human cells.

It’s also worth noting here that the Omicron variant carries the very same spike mutation that we studied in Alpha and Delta. Omicron also has another nearby change that might further alter O-glycosylation and cleavage of the spike protein by furin. The Ten Hagen lab is looking into these leads to learn how this region in Omicron affects spike glycosylation and, ultimately, the ability of this devastating virus to infect human cells and spread.


[1] Furin cleavage of the SARS-CoV-2 spike is modulated by O-glycosylation. Zhang L, Mann M, Syed Z, Reynolds HM, Tian E, Samara NL, Zeldin DC, Tabak LA, Ten Hagen KG. PNAS. 2021 Nov 23;118(47).


COVID-19 Research (NIH)

Kelly Ten Hagen (National Institute of Dental and Craniofacial Research/NIH)

Lawrence Tabak (NIDCR)

NIH Support: National Institute of Dental and Craniofacial Research

Biomedical Research Leads Science’s 2021 Breakthroughs

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Artificial Antibody Therapies, AI-Powered Predictions of Protein Structures, Antiviral Pills for COVID-19, and CRISPR Fixes Genes Inside the Body

Hi everyone, I’m Larry Tabak. I’ve served as NIH’s Principal Deputy Director for over 11 years, and I will be the acting NIH director until a new permanent director is named. In my new role, my day-to-day responsibilities will certainly increase, but I promise to carve out time to blog about some of the latest research progress on COVID-19 and any other areas of science that catch my eye.

I’ve also invited the directors of NIH’s Institutes and Centers (ICs) to join me in the blogosphere and write about some of the cool science in their research portfolios. I will publish a couple of posts to start, then turn the blog over to our first IC director. From there, I envision alternating between posts from me and from various IC directors. That way, we’ll cover a broad array of NIH science and the tremendous opportunities now being pursued in biomedical research.

Since I’m up first, let’s start where the NIH Director’s Blog usually begins each year: by taking a look back at Science’s Breakthroughs of 2021. The breakthroughs were formally announced in December near the height of the holiday bustle. In case you missed the announcement, the biomedical sciences accounted for six of the journal Science’s 10 breakthroughs. Here, I’ll focus on four biomedical breakthroughs, the ones that NIH has played some role in advancing, starting with Science’s editorial and People’s Choice top-prize winner:

Breakthrough of the Year: AI-Powered Predictions of Protein Structure

The biochemist Christian Anfinsen, who had a distinguished career at NIH, shared the 1972 Nobel Prize in Chemistry, for work suggesting that the biochemical interactions among the amino acid building blocks of proteins were responsible for pulling them into the final shapes that are essential to their functions. In his Nobel acceptance speech, Anfinsen also made a bold prediction: one day it would be possible to determine the three-dimensional structure of any protein based on its amino acid sequence alone. Now, with advances in applying artificial intelligence to solve biological problems—Anfinsen’s bold prediction has been realized.

But getting there wasn’t easy. Every two years since 1994, research teams from around the world have gathered to compete against each other in developing computational methods for predicting protein structures from sequences alone. A score of 90 or above means that a predicted structure is extremely close to what’s known from more time-consuming work in the lab. In the early days, teams more often finished under 60.

In 2020, a London-based company called DeepMind made a leap with their entry called AlphaFold. Their deep learning approach—which took advantage of 170,000 proteins with known structures—most often scored above 90, meaning it could solve most protein structures about as well as more time-consuming and costly experimental protein-mapping techniques. (AlphaFold was one of Science’s runner-up breakthroughs last year.)

This year, the NIH-funded lab of David Baker and Minkyung Baek, University of Washington, Seattle, Institute for Protein Design, published that their artificial intelligence approach, dubbed RoseTTAFold, could accurately predict 3D protein structures from amino acid sequences with only a fraction of the computational processing power and time that AlphaFold required [1]. They immediately applied it to solve hundreds of new protein structures, including many poorly known human proteins with important implications for human health.

The DeepMind and RoseTTAFold scientists continue to solve more and more proteins [1,2], both alone and in complex with other proteins. The code is now freely available for use by researchers anywhere in the world. In one timely example, AlphaFold helped to predict the structural changes in spike proteins of SARS-CoV-2 variants Delta and Omicron [3]. This ability to predict protein structures, first envisioned all those years ago, now promises to speed fundamental new discoveries and the development of new ways to treat and prevent any number of diseases, making it this year’s Breakthrough of the Year.

Anti-Viral Pills for COVID-19

The development of the first vaccines to protect against COVID-19 topped Science’s 2020 breakthroughs. This year, we’ve also seen important progress in treating COVID-19, including the development of anti-viral pills.

First, there was the announcement in October of interim data from Merck, Kenilworth, NJ, and Ridgeback Biotherapeutics, Miami, FL, of a significant reduction in hospitalizations for those taking the anti-viral drug molnupiravir [4] (originally developed with an NIH grant to Emory University, Atlanta). Soon after came reports of a Pfizer anti-viral pill that might target SARS-CoV-2, the novel coronavirus that causes COVID-19, even more effectively. Trial results show that, when taken within three days of developing COVID-19 symptoms, the pill reduced the risk of hospitalization or death in adults at high risk of progressing to severe illness by 89 percent [5].

On December 22, the Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for Pfizer’s Paxlovid to treat mild-to-moderate COVID-19 in people age 12 and up at high risk for progressing to severe illness, making it the first available pill to treat COVID-19 [6]. The following day, the FDA granted an EUA for Merck’s molnupiravir to treat mild-to-moderate COVID-19 in unvaccinated, high-risk adults for whom other treatment options aren’t accessible or recommended, based on a final analysis showing a 30 percent reduction in hospitalization or death [7].

Additional promising anti-viral pills for COVID-19 are currently in development. For example, a recent NIH-funded preclinical study suggests that a drug related to molnupiravir, known as 4’-fluorouridine, might serve as a broad spectrum anti-viral with potential to treat infections with SARS-CoV-2 as well as respiratory syncytial virus (RSV) [8].

Artificial Antibody Therapies

Before anti-viral pills came on the scene, there’d been progress in treating COVID-19, including the development of monoclonal antibody infusions. Three monoclonal antibodies now have received an EUA for treating mild-to-moderate COVID-19, though not all are effective against the Omicron variant [9]. This is also an area in which NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership has made big contributions.

Monoclonal antibodies are artificially produced versions of the most powerful antibodies found in animal or human immune systems, made in large quantities for therapeutic use in the lab. Until recently, this approach had primarily been put to work in the fight against conditions including cancer, asthma, and autoimmune diseases. That changed in 2021 with success using monoclonal antibodies against infections with SARS-CoV-2 as well as respiratory syncytial virus (RSV), human immunodeficiency virus (HIV), and other infectious diseases. This earned them a prominent spot among Science’s breakthroughs of 2021.

Monoclonal antibodies delivered via intravenous infusions continue to play an important role in saving lives during the pandemic. But, there’s still room for improvement, including new formulations highlighted on the blog last year that might be much easier to deliver.

CRISPR Fixes Genes Inside the Body

One of the most promising areas of research in recent years has been gene editing, including CRISPR/Cas9, for fixing misspellings in genes to treat or even cure many conditions. This year has certainly been no exception.

CRISPR is a highly precise gene-editing system that uses guide RNA molecules to direct a scissor-like Cas9 enzyme to just the right spot in the genome to cut out or correct disease-causing misspellings. Science highlights a small study reported in The New England Journal of Medicine by researchers at Intellia Therapeutics, Cambridge, MA, and Regeneron Pharmaceuticals, Tarrytown, NY, in which six people with hereditary transthyretin (TTR) amyloidosis, a condition in which TTR proteins build up and damage the heart and nerves, received an infusion of guide RNA and CRISPR RNA encased in tiny balls of fat [10]. The goal was for the liver to take them up, allowing Cas9 to cut and disable the TTR gene. Four weeks later, blood levels of TTR had dropped by at least half.

In another study not yet published, researchers at Editas Medicine, Cambridge, MA, injected a benign virus carrying a CRISPR gene-editing system into the eyes of six people with an inherited vision disorder called Leber congenital amaurosis 10. The goal was to remove extra DNA responsible for disrupting a critical gene expressed in the eye. A few months later, two of the six patients could sense more light, enabling one of them to navigate a dimly lit obstacle course [11]. This work builds on earlier gene transfer studies begun more than a decade ago at NIH’s National Eye Institute.

Last year, in a research collaboration that included former NIH Director Francis Collins’s lab at the National Human Genome Research Institute (NHGRI), we also saw encouraging early evidence in mice that another type of gene editing, called DNA base editing, might one day correct Hutchinson-Gilford Progeria Syndrome, a rare genetic condition that causes rapid premature aging. Preclinical work has even suggested that gene-editing tools might help deliver long-lasting pain relief. The technology keeps getting better, too. This isn’t the first time that gene-editing advances have landed on Science’s annual Breakthrough of the Year list, and it surely won’t be the last.

The year 2021 was a difficult one as the pandemic continued in the U.S. and across the globe, taking far too many lives far too soon. But through it all, science has been relentless in seeking and finding life-saving answers, from the rapid development of highly effective COVID-19 vaccines to the breakthroughs highlighted above.

As this list also attests, the search for answers has progressed impressively in other research areas during these difficult times. These groundbreaking discoveries are something in which we can all take pride—even as they encourage us to look forward to even bigger breakthroughs in 2022. Happy New Year!


[1] Accurate prediction of protein structures and interactions using a three-track neural network. Baek M, DiMaio F, Anishchenko I, Dauparas J, Grishin NV, Adams PD, Read RJ, Baker D., et al. Science. 2021 Jul 15:eabj8754.

[2] Highly accurate protein structure prediction with AlphaFold. Jumper J, Evans R, Pritzel A, Green T, Senior AW, Kavukcuoglu K, Kohli P, Hassabis D. et al. Nature. 2021 Jul 15.

[3] Structural insights of SARS-CoV-2 spike protein from Delta and Omicron variants. Sadek A, Zaha D, Ahmed MS. preprint bioRxiv. 2021 Dec 9.

[4] Merck and Ridgeback’s investigational oral antiviral molnupiravir reduced the risk of hospitalization or death by approximately 50 Percent compared to placebo for patients with mild or moderate COVID-19 in positive interim analysis of phase 3 study. Merck. 1 Oct 2021.

[5] Pfizer’s novel COVID-19 oral antiviral treatment candidate reduced risk of hospitalization or death by 89% in interim analysis of phase 2/3 EPIC-HR Study. Pfizer. 5 November 52021.

[6] Coronavirus (COVID-19) Update: FDA authorizes first oral antiviral for treatment of COVID-19. Food and Drug Administration. 22 Dec 2021.

[7] Coronavirus (COVID-19) Update: FDA authorizes additional oral antiviral for treatment of COVID-19 in certain adults. Food and Drug Administration. 23 Dec 2021.

[8] 4′-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replication. Sourimant J, Lieber CM, Aggarwal M, Cox RM, Wolf JD, Yoon JJ, Toots M, Ye C, Sticher Z, Kolykhalov AA, Martinez-Sobrido L, Bluemling GR, Natchus MG, Painter GR, Plemper RK. Science. 2021 Dec 2.

[9] Anti-SARS-CoV-2 monoclonal antibodies. NIH COVID-19 Treatment Guidelines. 16 Dec 2021.

[10] CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. Gillmore JD, Gane E, Taubel J, Kao J, Fontana M, Maitland ML, Seitzer J, O’Connell D, Walsh KR, Wood K, Phillips J, Xu Y, Amaral A, Boyd AP, Cehelsky JE, McKee MD, Schiermeier A, Harari O, Murphy A, Kyratsous CA, Zambrowicz B, Soltys R, Gutstein DE, Leonard J, Sepp-Lorenzino L, Lebwohl D. N Engl J Med. 2021 Aug 5;385(6):493-502.

[11] Editas Medicine announces positive initial clinical data from ongoing phase 1/2 BRILLIANCE clinical trial of EDIT-101 For LCA10. Editas Medicine. 29 Sept 2021.


Structural Biology (National Institute of General Medical Sciences/NIH)

The Structures of Life (NIGMS)

COVID-19 Research (NIH)

2021 Science Breakthrough of the Year (American Association for the Advancement of Science, Washington, D.C)

Latest on Omicron Variant and COVID-19 Vaccine Protection

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Graph. People with two shots and booster. 25 times more protection from Omicron
Credit: Adapted from Pfizer, Dec. 8, 2021

There’s been great concern about the new Omicron variant of SARS-CoV-2, the coronavirus that causes COVID-19. A major reason is Omicron has accumulated over 50 mutations, including about 30 in the spike protein, the part of the coronavirus that mRNA vaccines teach our immune systems to attack. All of these genetic changes raise the possibility that Omicron could cause breakthrough infections in people who’ve already received a Pfizer or Moderna mRNA vaccine.

So, what does the science show? The first data to emerge present somewhat encouraging results. While our existing mRNA vaccines still offer some protection against Omicron, there appears to be a significant decline in neutralizing antibodies against this variant in people who have received two shots of an mRNA vaccine.

However, initial results of studies conducted both in the lab and in the real world show that people who get a booster shot, or third dose of vaccine, may be better protected. Though these data are preliminary, they suggest that getting a booster will help protect people already vaccinated from breakthrough or possible severe infections with Omicron during the winter months.

Though Omicron was discovered in South Africa only last month, researchers have been working around the clock to learn more about this variant. Last week brought the first wave of scientific data on Omicron, including interesting work from a research team led by Alex Sigal, Africa Health Research Institute, Durban, South Africa [1].

In lab studies working with live Omicron virus, the researchers showed that this variant still relies on the ACE2 receptor to infect human lung cells. That’s really good news. It means that the therapeutic tools already developed, including vaccines, should generally remain useful for combatting this new variant.

Sigal and colleagues also tested the ability of antibodies in the plasma from 12 fully vaccinated individuals to neutralize Omicron. Six of the individuals had no history of COVID-19. The other six had been infected with the original variant in the first wave of infections in South Africa.

As expected, the samples showed very strong neutralization against the original SARS-CoV-2 variant. However, antibodies from people who’d been previously vaccinated with the two-dose Pfizer vaccine took a significant hit against Omicron, showing about a 40-fold decline in neutralizing ability.

This escape from immunity wasn’t complete. Indeed, blood samples from five individuals showed relatively good antibody levels against Omicron. All five had previously been infected with SARS-CoV-2 in addition to being vaccinated. These findings add to evidence on the value of full vaccination for protecting against reinfections in people who’ve had COVID-19 previously.

Also of great interest were the first results of the Pfizer study, which the company made available in a news release [2]. Pfizer researchers also conducted laboratory studies to test the neutralizing ability of blood samples from 19 individuals one month after a second shot compared to 20 others one month after a booster shot.

These studies showed that the neutralizing ability of samples from those who’d received two shots had a more than 25-fold decline relative to the original virus. Together with the South Africa data, it suggests that the two-dose series may not be enough to protect against breakthrough infections with the Omicron variant.

In much more encouraging news, their studies went on to show that a booster dose of the Pfizer vaccine raised antibody levels against Omicron to a level comparable to the two-dose regimen against the original variant (as shown in the figure above). While efforts already are underway to develop an Omicron-specific COVID-19 vaccine, these findings suggest that it’s already possible to get good protection against this new variant by getting a booster shot.

Very recently, real-world data from the United Kingdom, where Omicron cases are rising rapidly, are providing additional evidence for how boosters can help. In a preprint [3], Andrews et. al showed the effectiveness of two shots of Pfizer mRNA vaccine trended down after four months to about 40 percent. That’s not great, but note that 40 percent is far better than zero. So, clearly there is some protection provided.

Graph showing Pfizer booster is about 80% effective after 2 weeks against Omicron
Credit: Andrews N, et al., 2021

Most impressively (as shown in the figure from Andrews N, et al.) a booster substantially raised that vaccine effectiveness to about 80 percent. That’s not quite as high as for Delta, but certainly an encouraging result. Once again, these data show that boosting the immune system after a pause produces enhanced immunity against new viral variants, even though the booster was designed from the original virus. Your immune system is awfully clever. You get both quantitative and qualitative benefits.

It’s also worth noting that the Omicron variant mostly doesn’t have mutations in portions of its genome that are the targets of other aspects of vaccine-induced immunity, including T cells. These cells are part of the body’s second line of defense and are generally harder for viruses to escape. While T cells can’t prevent infection, they help protect against more severe illness and death.

It’s important to note that scientists around the world are also closely monitoring Omicron’s severity While this variant appears to be highly transmissible, and it is still early for rigorous conclusions, the initial research indicates this variant may actually produce milder illness than Delta, which is currently the dominant strain in the United States.

But there’s still a tremendous amount of research to be done that could change how we view Omicron. This research will take time and patience.

What won’t change, though, is that vaccines are the best way to protect yourself and others against COVID-19. (And these recent data provide an even-stronger reason to get a booster now if you are eligible.) Wearing a mask, especially in public indoor settings, offers good protection against the spread of all SARS-CoV-2 variants. If you’ve got symptoms or think you may have been exposed, get tested and stay home if you get a positive result. As we await more answers, it’s as important as ever to use all the tools available to keep yourself, your loved ones, and your community happy and healthy this holiday season.


[1] SARS-CoV-2 Omicron has extensive but incomplete escape of Pfizer BNT162b2 elicited neutralization and requires ACE2 for infection. Sandile C, et al. Sandile C, et al. medRxiv preprint. December 9, 2021.

[2] Pfizer and BioNTech provide update on Omicron variant. Pfizer. December 8, 2021.

[3] Effectiveness of COVID-19 vaccines against the Omicron (B.1.1.529) variant of concern. Andrews N, et al. preprint. December 10, 2021.


COVID-19 Research (NIH)

Sigal Lab (Africa Health Research Institute, Durban, South Africa)

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