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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.

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


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!

References:

[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.

Links:

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., KHub.net 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.

References:

[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. KHub.net preprint. December 10, 2021.

Links:

COVID-19 Research (NIH)

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


Feeling Grateful This Thanksgiving for Biomedical Research

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Credit: Lucky Business/Shutterstock

Yes, we can all agree that 2021 has been a tough year. But despite all that, Thanksgiving is the right time to stop and count our many blessings. My list starts with my loving wife Diane and family, all of whom have been sources of encouragement in these trying times. But also high up on the list this Thanksgiving is my extreme gratitude to the scientific community for all the research progress that has been made over the past 23 months to combat the pandemic and return our lives ever closer to normal.

Last year, we were busy learning how to celebrate a virtual Thanksgiving. This year, most of us are feeling encouraged about holding face-to-face gatherings once again—but carefully!—and coordinating which dishes to prepare for the annual feast.

The COVID-19 vaccines, developed by science in record time and with impressive safety and effectiveness, have made this possible. The almost 230 million Americans who have chosen to receive at least one dose of a COVID-19 vaccine have taken a critical step to protect themselves and others. They have made this season a much safer one for themselves and those around them than a year ago. That includes almost all adults ages 65 and up. While vaccination rates aren’t yet as high as they need to be in younger age groups, about 70 percent of Americans ages 12 and up are now fully vaccinated.

But with evidence that the effectiveness of the vaccines can wane over time and with the continued threat of the Delta variant, I was happy to see the recent approval by both FDA and CDC that all adults 18 and over are now eligible to receive a booster. That is, provided you are now more than 6 months past your initial immunization with the Moderna or Pfizer or 2 months past your immunization with the Johnson & Johnson vaccine. I recently got my Moderna booster and I’m glad for that additional protection. Don’t wait—the booster is the best way to defend against a possible winter surge.

Children age 5 and up are also now eligible to get the Pfizer vaccine, a development that I know brought a sense of relief and gratitude for many parents with school-aged children at home. It will take a little time for full vaccination of this age group. But more than 2.5 million young kids around the country already have rolled up their sleeves and have some immunity against COVID-19. These children are on track to be fully vaccinated before Christmas.

I’m also extremely grateful for all the progress that’s been made in treating COVID-19. Developing new treatments typically takes many years, if not decades. But NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative, a public-private partnership involving 20 biopharmaceutical companies, academic experts, and multiple federal agencies, has helped lead the way to this rapid progress.

We’ve seen successes in the use of monoclonal antibodies and in the repurposing of existing drugs, such as blood thinning treatments, to keep folks hospitalized with COVID-19 from becoming severely ill and needing some form of organ support. Now it looks as though our hopes for safe and effective oral antiviral medicines to reduce the risk of severe illness in individuals just diagnosed with COVID-19 could soon be realized, too.

To combat COVID-19, rapid and readily accessible testing also is key, and NIH’s Rapid Acceleration of Diagnostics (RADx®) initiative continues to speed innovation in COVID-19 testing. RADx® also recently launched a simple online calculator tool to help individuals make critical decisions about when to get a test [1]. Meanwhile, a new initiative called Say Yes! COVID Test (SYCT) is exploring how best to implement home-testing programs in our communities.

More research progress is on the way. But, until the pandemic is history, please remember to stay safe this holiday season. The best way to do so is to get fully vaccinated [2]. As I noted above, most adults who got vaccinated earlier this year are now eligible for a booster shot to ensure they remain well protected. Go to vaccines.gov to find the site closest to you that can provide the shot.

The best way to protect young children who aren’t yet eligible or fully vaccinated and others who may be at higher risk is by making sure you and others around them are vaccinated. It’s still strongly recommended to wear a well-fitting mask over your nose and mouth when in public indoor settings, especially if there’s considerable spread of COVID-19 in your community.

If you are gathering with multiple households or people from different parts of the country, consider getting tested for COVID-19 in advance and take extra precautions before traveling. By taking full advantage of all the many scientific advances we’ve made over the last year, we can now feel good about celebrating together again this holiday season. Happy Thanksgiving!

References:

[1] When to Test offers free online tool to help individuals make informed COVID-19 testing decisions. National Institutes of Health. November 3, 2021.

[2] Safer ways to celebrate holidays. Centers for Disease Control and Prevention. October 15, 2021.

Links:

COVID-19 Research (NIH)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)

Rapid Acceleration of Diagnostics (RADx®) (NIH)

When To Test (Consortia for Improving Medicine with Innovation & Technology, Boston)


Early Data Suggest Pfizer Pill May Prevent Severe COVID-19

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Woman holding a pill bottle. Chemical molecular structure is nearby
Credit: Fizkes/Shutterstock

Over the course of this pandemic, significant progress has been made in treating COVID-19 and helping to save lives. That progress includes the development of life-preserving monoclonal antibody infusions and repurposing existing drugs, to which NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership has made a major contribution.

But for many months we’ve had hopes that a safe and effective oral medicine could be developed that would reduce the risk of severe illness for individuals just diagnosed with COVID-19. The first indication that those hopes might be realized came from the announcement just a month ago of a 50 percent reduction in hospitalizations from the Merck and Ridgeback drug molnupiravir (originally developed with an NIH grant to Emory University, Atlanta). Now comes word of a second drug with potentially even higher efficacy: an antiviral pill from Pfizer Inc. that targets a different step in the life cycle of SARS-CoV-2, the novel coronavirus that causes COVID-19.

The most recent exciting news started to roll out earlier this month when a Pfizer research team published in the journal Science some promising initial data involving the antiviral pill and its active compound [1]. Then came even bigger news a few days later when Pfizer announced interim results from a large phase 2/3 clinical trial. It found that, when taken within three days of developing symptoms of COVID-19, the pill reduced by 89 percent the risk of hospitalization or death in adults at high risk of progressing to severe illness [2].

At the recommendation of the clinical trial’s independent data monitoring committee and in consultation with the U.S. Food and Drug Administration (FDA), Pfizer has now halted the study based on the strength of the interim findings. Pfizer plans to submit the data to the FDA for Emergency Use Authorization (EUA) very soon.

Pfizer’s antiviral pill is a protease inhibitor, originally called PF-07321332, or just 332 for short. A protease is an enzyme that cleaves a protein at a specific series of amino acids. The SARS-CoV-2 virus encodes its own protease to help process a large virally-encoded polyprotein into smaller segments that it needs for its life cycle; a protease inhibitor drug can stop that from happening. If the term protease inhibitor rings a bell, that’s because drugs that work in this way already are in use to treat other viruses, including human immunodeficiency virus (HIV) and hepatitis C virus.

In the case of 332, it targets a protease called Mpro, also called the 3CL protease, coded for by SARS-CoV-2. The virus uses this enzyme to snip some longer viral proteins into shorter segments for use in replication. With Mpro out of action, the coronavirus can’t make more of itself to infect other cells.

What’s nice about this therapeutic approach is that mutations to SARS-CoV-2’s surface structures, such as the spike protein, should not affect a protease inhibitor’s effectiveness. The drug targets a highly conserved, but essential, viral enzyme. In fact, Pfizer originally synthesized and pre-clinically evaluated protease inhibitors years ago as a potential treatment for severe acute respiratory syndrome (SARS), which is caused by a coronavirus closely related to SARS-CoV-2. This drug might even have efficacy against other coronaviruses that cause the common cold.

In the study published earlier this month in Science [1], the Pfizer team led by Dafydd Owen, Pfizer Worldwide Research, Cambridge, MA, reported that the latest version of their Mpro inhibitor showed potent antiviral activity in laboratory tests against not just SARS-CoV-2, but all of the coronaviruses they tested that are known to infect people. Further study in human cells and mouse models of SARS-CoV-2 infection suggested that the treatment might work to limit infection and reduce damage to lung tissue.

In the paper in Science, Owen and colleagues also reported the results of a phase 1 clinical trial with six healthy people. They found that their protease inhibitor, when taken orally, was safe and could reach concentrations in the bloodstream that should be sufficient to help combat the virus.

But would it work to treat COVID-19 in an infected person? So far, the preliminary results from the larger clinical trial of the drug candidate, now known as PAXLOVID™, certainly look encouraging. PAXLOVID™ is a formulation that combines the new protease inhibitor with a low dose of an existing drug called ritonavir, which slows the metabolism of some protease inhibitors and thereby keeps them active in the body for longer periods of time.

The phase 2/3 clinical trial included about 1,200 adults from the United States and around the world who had enrolled in the clinical trial. To be eligible, study participants had to have a confirmed diagnosis of COVID-19 within a five-day period along with mild-to-moderate symptoms of illness. They also required at least one characteristic or condition associated with an increased risk for developing severe illness from COVID-19. Each individual in the study was randomly selected to receive either the experimental antiviral or a placebo every 12 hours for five days.

In people treated within three days of developing COVID-19 symptoms, the Pfizer announcement reports that 0.8 percent (3 of 389) of those who received PAXLOVID™ were hospitalized within 28 days compared to 7 percent (27 of 385) of those who got the placebo. Similarly encouraging results were observed in those who got the treatment within five days of developing symptoms. One percent (6 of 607) on the antiviral were hospitalized versus 6.7 percent (41 of 612) in the placebo group. Overall, there were no deaths among people taking PAXLOVID™; 10 people in the placebo group (1.6 percent) subsequently died.

If all goes well with the FDA review, the hope is that PAXLOVID™ could be prescribed as an at-home treatment to prevent severe illness, hospitalization, and deaths. Pfizer also has launched two additional trials of the same drug candidate: one in people with COVID-19 who are at standard risk for developing severe illness and another evaluating its ability to prevent infection in adults exposed to the coronavirus by a household member.

Meanwhile, Britain recently approved the other recently developed antiviral molnupiravir, which slows viral replication in a different way by blocking its ability to copy its RNA genome accurately. The FDA will meet on November 30 to discuss Merck and Ridgeback’s request for an EUA for molnupiravir to treat mild-to-moderate COVID-19 in infected adults at high risk for severe illness [3]. With Thanksgiving and the winter holidays fast approaching, these two promising antiviral drugs are certainly more reasons to be grateful this year.

References:

[1] An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19.
Owen DR, Allerton CMN, Anderson AS, Wei L, Yang Q, Zhu Y, et al. Science. 2021 Nov 2: eabl4784.

[2] 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. November 5, 2021.

[3] FDA to hold advisory committee meeting to Discuss Merck and Ridgeback’s EUA Application for COVID-19 oral treatment. Food and Drug Administration. October 14, 2021.

Links:

COVID-19 Research (NIH)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)

A Study of PF-07321332/Ritonavir in Nonhospitalized Low-Risk Adult Participants With COVID-19 (ClinicalTrials.gov)

A Post-Exposure Prophylaxis Study of PF-07321332/Ritonavir in Adult Household Contacts of an Individual With Symptomatic COVID-19 (ClinicalTrials.gov)


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