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One of the world’s earliest farming villages housed surprisingly few people

Hundreds, not thousands, occupied the Turkish site of Çatalhöyük nearly 9,000 years ago, undermining arguments for a Neolithic social revolution.

‘The High Seas’ tells of the many ways humans are laying claim to the ocean

Burning the stomach lining reduces the ‘hunger hormone’ and cuts weight 

Sumatran orangutans start crafting their engineering skills as infants

The heart plays a hidden role in our mental health

Genetic analyses of the bird flu virus unveil its evolution and potential

How smart was T. rex ?

Trending stories.

A new look at Ötzi the Iceman’s DNA reveals new ancestry and other surprises

How did an ancient shark parasite end up fossilized in tree resin?

The universe may have a complex geometry — like a doughnut

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Spotlight on Health

Traces of bird flu are showing up in cow milk. Here’s what to know

We asked the experts: Should people be worried? Pasteurization and the H5N1 virus’s route to infection suggests risks to people remains low.

Irregular bone marrow cells may increase heart disease risk

Malaria parasites can evade rapid tests, threatening eradication goals, from the archives.

Human Behavior: Do Animals Have the Answer

April 27, 1974 Vol. 105 No. #17

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A hidden danger lurks beneath Yellowstone

A vaccine for bees has an unexpected effect, how ötzi the iceman really got his tattoos.

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Eavesdropping on fish could help us keep better tabs on underwater worlds

Scientists are on a quest to log all the sounds of fish communication. The result could lead to better monitoring of ecosystems and fish behavior.

Tiny treadmills show how fruit flies walk

Explore a map of the next 15 total solar eclipses

This robot can tell when you’re about to smile — and smile back

Rain Bosworth studies how deaf children experience the world

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This marine alga is the first known eukaryote to pull nitrogen from air

During a total solar eclipse, some colors really pop. here’s why.

These are the chemicals that give teens pungent body odor

Here’s why covid-19 isn’t seasonal so far, human embryo replicas have gotten more complex. here’s what you need to know.

As the Arctic tundra warms, soil microbes likely will ramp up CO 2 production

A ruinous hailstorm in spain may have been supercharged by warming seas, three reasons why the ocean’s record-breaking hot streak is devastating.

How a 19th century astronomer can help you watch the total solar eclipse

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Newfound ‘altermagnets’ shatter the magnetic status quo 

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Extreme heat will put millions more older adults at risk in the future

Cows might host both human and bird flus, a new gel stops mice from getting too drunk.

A weaker magnetic field may have paved the way for marine life to go big

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Language models may miss signs of depression in Black people’s Facebook posts

In ‘get the picture,’ science helps explore the meaning of art, what  science news  saw during the solar eclipse.

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A sea otter in Monterey Bay with a rock anvil on its belly and a scallop in its forepaws. Jessica Fujii hide caption

When sea otters lose their favorite foods, they can use tools to go after new ones

May 20, 2024 • Some otters rely on tools to bust open hard-shelled prey items like snails, and a new study suggests this tool use is helping them to survive as their favorite, easier-to-eat foods disappear.

Lauren Hill, a graduate student at Cal State LA, holds a bird at the bird banding site at Bear Divide in the San Gabriel Mountains. Grace Widyatmadja/NPR hide caption

On this unassuming trail near LA, bird watchers see something spectacular

May 13, 2024 • At Bear Divide, just outside Los Angeles, you can see a rare spectacle of nature. This is one of the only places in the western United States where you can see bird migration during daylight hours.

The inside of a cell is a complicated orchestration of interactions between molecules. Keith Chambers/Science Photo Library hide caption

AI gets scientists one step closer to mapping the organized chaos in our cells

May 13, 2024 • As artificial intelligence seeps into some realms of society, it rushes into others. One area it's making a big difference is protein science — as in the "building blocks of life," proteins! Producer Berly McCoy talks to host Emily Kwong about the newest advance in protein science: AlphaFold3, an AI program from Google DeepMind. Plus, they talk about the wider field of AI protein science and why researchers hope it will solve a range of problems, from disease to the climate.

NASA's Solar Dynamics Observatory captured this image of a strong solar flare on May 8, 2024. The Wednesday solar flares kicked off the geomagnetic storm happening this weekend. NASA/SDO hide caption

NOAA Issues First Severe Geomagnetic Storm Watch Since 2005

May 10, 2024 • Scientists at the National Oceanic and Atmospheric Administration observed a cluster of sunspots on the surface of the sun this week. With them came solar flares that kicked off a severe geomagnetic storm. That storm is expected to last throughout the weekend as at least five coronal mass ejections — chunks of the sun — are flung out into space, towards Earth! NOAA uses a five point scale to rate these storms, and this weekend's storm is a G4. It's expected to produce auroras as far south as Alabama. To contextualize this storm, we are looking back at the largest solar storm on record: the Carrington Event.

Esther Nesbitt lost two of her children to drug overdoses, and her grandchildren are among more than 320,000 who lost parents in the overdose epidemic. Andrew Lichtenstein/Corbis via Getty Images hide caption

Shots - Health News

In a decade of drug overdoses, more than 320,000 american children lost a parent.

May 8, 2024 • New research documents how many children lost a parent to an opioid or other overdose in the period from 2011 to 2021. Bereaved children face elevated risks to their physical and emotional health.

This illustration depicts a washed-up Ichthyotitan severnensis carcass on the beach. Sergey Krasovskiy hide caption

Largest-ever marine reptile found with help from an 11-year-old girl

May 6, 2024 • A father and daughter discovered fossil remnants of a giant ichthyosaur that scientists say may have been the largest-known marine reptile to ever swim the seas.

A survey shows that doctors have trouble taking full vacations from their high-stress jobs. Even when they do, they often still do work on their time off. Wolfgang Kaehler/LightRocket via Getty Images hide caption

Perspective

When pto stands for 'pretend time off': doctors struggle to take real breaks.

May 4, 2024 • What's a typical vacation activity for doctors? Work. A new study finds that most physicians do work on a typical day off. In this essay, a family doctor considers why that is and why it matters.

Weliton Menário Costa (center) holds a laptop while surrounded by dancers for his music video, "Kangaroo Time." From left: Faux Née Phish (Caitlin Winter), Holly Hazlewood, and Marina de Andrade. Nic Vevers/ANU hide caption

'Dance Your Ph.D.' winner on science, art, and embracing his identity

May 4, 2024 • Weliton Menário Costa's award-winning music video showcases his research on kangaroo personality and behavior — and offers a celebration of human diversity, too.

Researchers in a rainforest in Indonesia spotted an injury on the face of a male orangutan they named Rakus. They were stunned to watch him treat his wound with a medicinal plant. Armas/Suaq Project hide caption

Orangutan in the wild applied medicinal plant to heal its own injury, biologists say

May 3, 2024 • It is "the first known case of active wound treatment in a wild animal with a medical plant," biologist Isabelle Laumer told NPR. She says the orangutan, called Rakus, is now thriving.

The federal government says it has taken steps toward developing a vaccine to protect against bird flu should it become a threat to humans. skodonnell/Getty Images hide caption

Launching an effective bird flu vaccine quickly could be tough, scientists warn

May 3, 2024 • Federal health officials say the U.S. has the building blocks to make a vaccine to protect humans from bird flu, if needed. But experts warn we're nowhere near prepared for another pandemic.

A Nazca booby in the Galápagos Islands incubates eggs with its webbed feet. Wolfgang Kaehler/LightRocket via Getty Images hide caption

The Science of Siblings

For birds, siblinghood can be a matter of life or death.

May 1, 2024 • Some birds kill their siblings soon after hatching. Other birds spend their whole lives with their siblings and will even risk their lives to help each other.

Planet Money

How do you counter misinformation critical thinking is step one.

April 30, 2024 • An economic perspective on misinformation

This image shows a brain "assembloid" consisting of two connected brain "organoids." Scientists studying these structures have restored impaired brain cells in Timothy syndrome patients. Pasca lab, Stanford University hide caption

Scientists restore brain cells impaired by a rare genetic disorder

April 30, 2024 • A therapy that restores brain cells impaired by a rare genetic disorder may offer a strategy for treating conditions like autism, epilepsy, and schizophrenia.

Katie Krimitsos is among the majority of American women who have trouble getting healthy sleep, according to a new Gallup survey. Krimitsos launched a podcast called Sleep Meditation for Women to offer some help. Natalie Champa Jennings/Natalie Jennings, courtesy of Katie Krimitsos hide caption

Helping women get better sleep by calming the relentless 'to-do lists' in their heads

April 26, 2024 • A recent survey found that Americans' sleep patterns have been getting worse. Adult women under 50 are among the most sleep-deprived demographics.

Bird flu is spreading through U.S. dairy cattle. Scientists say the risk to people is minimal, but open questions remain, including how widespread the outbreak is and how the virus is spreading. DOUGLAS MAGNO/AFP via Getty Images hide caption

As bird flu spreads in cows, here are 4 big questions scientists are trying to answer

April 26, 2024 • Health officials say there's very little risk to humans from the bird flu outbreak among dairy cattle, but there's still much they don't know. Here are four questions scientists are trying to answer.

A coyote at the Fort Worth Zoo is photographed in the hours leading up to the April 8 total solar eclipse. The Hartstone-Rose Research Lab, NC State hide caption

Animals get stressed during eclipses. But not for the reason you think

April 25, 2024 • After studying various species earlier this month, some scientists now say they understand the origin of animal behavior during solar eclipses.

Dr. Jeffrey Stern, assistant professor in the Department of Surgery at NYU Grossman School of Medicine, and Dr. Robert Montgomery, director of the NYU Langone Transplant Institute, prepare the gene-edited pig kidney with thymus for transplantation. Joe Carrotta for NYU Langone Health hide caption

A woman with failing kidneys receives genetically modified pig organs

April 24, 2024 • Surgeons transplanted a kidney and thymus gland from a gene-edited pig into a 54-year-old woman in an attempt to extend her life. It's the latest experimental use of animal organs in humans.

Drug companies often do one-on-one outreach to doctors. A new study finds these meetings with drug reps lead to more prescriptions for cancer patients, but not longer survival. Chris Hondros/Getty Images hide caption

Oncologists' meetings with drug reps don't help cancer patients live longer

April 22, 2024 • Drug company reps commonly visit doctors to talk about new medications. A team of economists wanted to know if that helps patients live longer. They found that for cancer patients, the answer is no.

When the media covers scientific research, not all scientists are equally likely to be mentioned. A new study finds scientists with Asian or African names were 15% less likely to be named in a story. shironosov/Getty Images hide caption

Which scientists get mentioned in the news? Mostly ones with Anglo names, says study

April 19, 2024 • A new study finds that in news stories about scientific research, U.S. media were less likely to mention a scientist if they had an East Asian or African name, as compared to one with an Anglo name.

An artistic rendering of a washed-up Ichthyotitan severnensis carcass on the beach. Sergey Krasovskiy hide caption

An 11-year-old unearthed fossils of the largest known marine reptile

April 19, 2024 • When the dinosaurs walked the Earth, massive marine reptiles swam. Among them, a species of Ichthyosaur that measured over 80 feet long. Today, we look into how a chance discovery by a father-daughter duo of fossil hunters furthered paleontologist's understanding of the "giant fish lizard of the Severn." Currently, it is the largest marine reptile known to scientists.

COMIC: Our sun was born with thousands of other stars. Where did they all go?

April 18, 2024 • Our sun was born in a cosmic cradle with thousands of other stars. Astrophysicists say they want to find these siblings in order to help answer the question: Are we alone out there?

Surgeon Christoph Haller and his research team from Toronto's Hospital for Sick Children are working on technology that could someday result in an artificial womb to help extremely premature babies. Chloe Ellingson for NPR hide caption

An artificial womb could build a bridge to health for premature babies

April 12, 2024 • Artificial wombs could someday save babies born very prematurely. Even though the experimental technology is still in animal tests, there are mounting questions about its eventual use with humans.

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Top 10 research topics from 2021.

Find the answers to your biggest research questions from 2021. With collective views of over 3.7 million, researchers explored topics spanning from nutritional immunology and political misinformation to sustainable agriculture and the human-dog bond .

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1. Infectious disease

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2. Nutritional immunology

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December 22, 2021

2021 Research Highlights — Promising Medical Findings

Results with potential for enhancing human health.

With NIH support, scientists across the United States and around the world conduct wide-ranging research to discover ways to enhance health, lengthen life, and reduce illness and disability. Groundbreaking NIH-funded research often receives top scientific honors. In 2021, these honors included Nobel Prizes to five NIH-supported scientists . Here’s just a small sample of the NIH-supported research accomplishments in 2021.

Printer-friendly version of full 2021 NIH Research Highlights

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Advancing COVID-19 treatment and prevention

Amid the sustained pandemic, researchers continued to develop new drugs and vaccines for COVID-19. They found oral drugs that could  inhibit virus replication in hamsters and shut down a key enzyme that the virus needs to replicate. Both drugs are currently in clinical trials. Another drug effectively treated both SARS-CoV-2 and RSV, another serious respiratory virus, in animals. Other researchers used an airway-on-a-chip to screen approved drugs for use against COVID-19. These studies identified oral drugs that could be administered outside of clinical settings. Such drugs could become powerful tools for fighting the ongoing pandemic. Also in development are an intranasal vaccine , which could help prevent virus transmission, and vaccines that can protect against a range of coronaviruses .

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Developments in Alzheimer’s disease research

One of the hallmarks of Alzheimer’s is an abnormal buildup of amyloid-beta protein. A study in mice suggests that antibody therapies targeting amyloid-beta protein could be more effective after enhancing the brain’s waste drainage system . In another study, irisin, an exercise-induced hormone, was found to improve cognitive performance in mice . New approaches also found two approved drugs (described below) with promise for treating AD. These findings point to potential strategies for treating Alzheimer’s. Meanwhile, researchers found that people who slept six hours or less per night in their 50s and 60s were more likely to develop dementia later in life, suggesting that inadequate sleep duration could increase dementia risk.

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New uses for old drugs

Developing new drugs can be costly, and the odds of success can be slim. So, some researchers have turned to repurposing drugs that are already approved for other conditions. Scientists found that two FDA-approved drugs were associated with lower rates of Alzheimer’s disease. One is used for high blood pressure and swelling. The other is FDA-approved to treat erectile dysfunction and pulmonary hypertension. Meanwhile, the antidepressant fluoxetine was associated with reduced risk of age-related macular degeneration. Clinical trials will be needed to confirm these drugs’ effects.

20210713-heart.jpg

Making a wireless, biodegradable pacemaker

Pacemakers are a vital part of medical care for many people with heart rhythm disorders. Temporary pacemakers currently use wires connected to a power source outside the body. Researchers developed a temporary pacemaker that is powered wirelessly. It also breaks down harmlessly in the body after use. Studies showed that the device can generate enough power to pace a human heart without causing damage or inflammation.

20210330-crohns.jpg

Fungi may impair wound healing in Crohn’s disease

Inflammatory bowel disease develops when immune cells in the gut overreact to a perceived threat to the body. It’s thought that the microbiome plays a role in this process. Researchers found that a fungus called  Debaryomyces hansenii  impaired gut wound healing in mice and was also found in damaged gut tissue in people with Crohn’s disease, a type of inflammatory bowel disease. Blocking this microbe might encourage tissue repair in Crohn’s disease.

20210406-flu.jpg

Nanoparticle-based flu vaccine

Influenza, or flu, kills an estimated 290,000-650,000 people each year worldwide. The flu virus changes, or mutates, quickly. A single vaccine that conferred protection against a wide variety of strains would provide a major boost to global health. Researchers developed a nanoparticle-based vaccine that protected against a broad range of flu virus strains in animals. The vaccine may prevent flu more effectively than current seasonal vaccines. Researchers are planning a Phase 1 clinical trial to test the vaccine in people.

20211002-lyme.jpg

A targeted antibiotic for treating Lyme disease

Lyme disease cases are becoming more frequent and widespread. Current treatment entails the use of broad-spectrum antibiotics. But these drugs can damage the patient’s gut microbiome and select for resistance in non-target bacteria. Researchers found that a neglected antibiotic called hygromycin A selectively kills the bacteria that cause Lyme disease. The antibiotic was able to treat Lyme disease in mice without disrupting the microbiome and could make an attractive therapeutic candidate.

20211102-back.jpg

Retraining the brain to treat chronic pain

More than 25 million people in the U.S. live with chronic pain. After a treatment called pain reprocessing therapy, two-thirds of people with mild or moderate chronic back pain for which no physical cause could be found were mostly or completely pain-free. The findings suggest that people can learn to reduce the brain activity causing some types of chronic pain that occur in the absence of injury or persist after healing.

2021 Research Highlights — Basic Research Insights >>

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New potential therapeutic target identified for Crohn’s disease

New research has shed light on how known genetic risk factors can contribute to Crohn’s disease and treatment response, opening the door to new treatment approaches. Crohn’s disease is a form of inflammatory bowel disease in which the digestive tract is marked by lesions of damaging inflammation. It can start at any age, causing lifelong episodes of cramping, diarrhea, and malnutrition. Medications that block a major component of the inflammatory response called tumor necrosis factor (TNF) are effective for many people, but in some cases the disease does not respond to these drugs. Among the scores of genetic variations that have been linked to a higher risk for developing Crohn’s disease, changes in a gene called NOD2 that impair its function have been found to be a major risk factor. Exactly how these NOD2 genetic variations could contribute to Crohn’s disease has been unclear, however, which has been a major roadblock for developing new therapies.

Researchers set out to answer this question by analyzing intestinal samples from a well-characterized group of male and female children with Crohn’s disease. They found that genetic variations inhibiting NOD2 function were linked to changes in fibroblasts (cells that make up connective tissue) and immune cells in Crohn’s disease lesions. Specifically, these cell types showed signs that they were “activated” and producing factors involved in inflammation. Importantly, activated immune cells and fibroblasts have also been found in lesions from people with refractory Crohn’s disease that is resistant to anti-TNF therapy, suggesting that these activated cells provide an additional route to inflammation that is independent of TNF-mediated inflammation. Using cultured cells and a zebrafish model that effectively mimics human Crohn’s disease, the researchers identified a protein known as gp130 that plays a critical role in activating these cells when NOD2 is impaired. Data from women and men with Crohn’s disease that did not respond well to anti-TNF therapy showed high levels of intestinal proteins in the cellular pathway used by gp130. Additionally, the researchers found that treating zebrafish or cultured cells with a gp130-blocking drug inhibits activation of inflammatory cells. More research is needed to determine if blocking gp130 will similarly reduce cellular activation in human intestinal lesions. However, this study suggests that drugs targeting gp130, when used in conjunction with anti-TNF therapy, might be effective treatments for people with Crohn’s disease resulting from NOD2 risk variants.

Nayar S, Morrison JK, Giri M,…Cho JH. A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn's disease . Nature 593: 275-281, 2021.

Breakthrough in search for tinnitus cure

Scientists are excited by results from a trial of a new treatment for tinnitus.

After 20 years searching for a cure for tinnitus, researchers at the University of Auckland are excited by 'encouraging results' from a clinical trial of a mobile-phone-based therapy. The study randomised 61 patients to one of two treatments, the prototype of the new 'digital polytherapeutic' or a popular self-help app producing white noise.

On average, the group with the polytherapeutic (31 people) showed clinically significant improvements at 12 weeks, while the other group (30 people) did not. The results have just been published in Frontiers in Neurology . "This is more significant than some of our earlier work and is likely to have a direct impact on future treatment of tinnitus," Associate Professor in Audiology Grant Searchfield says.

Key to the new treatment is an initial assessment by an audiologist who develops the personalised treatment plan, combining a range of digital tools, based on the individual's experience of tinnitus. "Earlier trials have found white noise, goal-based counselling, goal-oriented games and other technology-based therapies are effective for some people some of the time," says Dr Searchfield. "This is quicker and more effective, taking 12 weeks rather than 12 months for more individuals to gain some control."

There is no pill that can cure tinnitus. "What this therapy does is essentially rewire the brain in a way that de-emphasises the sound of the tinnitus to a background noise that has no meaning or relevance to the listener," Dr Searchfield says.

Audiology research fellow Dr Phil Sanders says the results are exciting and he found running the trial personally rewarding.

"Sixty-five percent of participants reported an improvement. For some people, it was life-changing -- where tinnitus was taking over their lives and attention."

Some people didn't notice an improvement and their feedback will inform further personalisation, Dr Sanders says.

Tinnitus is a phantom noise and its causes are complex. It has so far defied successful treatment.

While most people experience tinnitus, or ringing in the ears at least on occasions, around five percent experience it to a distressing degree. Impacts can include trouble sleeping, difficulty carrying out daily tasks and depression.

Dr Searchfield says seeing his patients' distress and having no effective treatment to offer inspired his research. "I wanted to make a difference."

The next step will be to refine the prototype and proceed to larger local and international trials with a view to FDA approval.

The researchers hope the app will be clinically available in around six months.

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Story Source:

Materials provided by University of Auckland . Note: Content may be edited for style and length.

Journal Reference :

• Grant D. Searchfield, Philip J. Sanders. A randomized single-blind controlled trial of a prototype digital polytherapeutic for tinnitus . Frontiers in Neurology , 2022; 13 DOI: 10.3389/fneur.2022.958730

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Western researchers’ breakthrough paves way for ALS cure

Fueled by a $10-million gift from the temerty foundation, a possible new als treatment could move to clinical trials within five years.

By Prabhjot Sohal

In a groundbreaking Canadian discovery powered by philanthropy, a team of Western University researchers led by Dr. Michael Strong has uncovered a potential path toward a cure for amyotrophic lateral sclerosis (ALS). 

The breakthrough, which illustrates how protein interactions can preserve or prevent the nerve cell death that is a hallmark of ALS, is the culmination of decades of Western research backed by the Temerty Foundation.

“As a doctor, it’s been so important for me to be able to sit down with a patient or their family and say to them, ‘we're trying to stop this disease,’” said Strong, a clinician-scientist who has devoted his career to finding a cure for ALS. “It's been 30 years of work to get here; 30 years of looking after families and patients and their loved ones, when all we had was hope. This gives us reason to believe we've discovered a path to treatment.”

ALS, also known as Lou Gehrig’s disease, is a debilitating neurodegenerative condition that progressively impairs nerve cells responsible for muscle control, leading to muscle wastage, paralysis and, ultimately, death. The average life expectancy of an ALS patient post-diagnosis is a mere two to five years.

In a study recently published in the journal Brain , Strong’s team found that targeting an interaction between two proteins present in ALS-impacted nerve cells can halt or reverse the disease’s progression. The team also identified a mechanism to make this possible.

“ This gives us reason to believe we've discovered a path to treatment.” —Dr. Michael Strong

“Importantly, this interaction could be key to unlocking a treatment not just for ALS but also for other related neurological conditions, like frontotemporal dementia,” said Strong, who holds the Arthur J. Hudson Chair in ALS Research at Western’s Schulich School of Medicine & Dentistry. “It is a gamechanger.”

In virtually all ALS patients, a protein called TDP-43 is responsible for forming abnormal clumps within cells, which causes cell death. In recent years, Strong’s team discovered a second protein, called RGNEF, with functions that are opposite to TDP-43.

The team’s latest breakthrough identifies a specific fragment of that RGNEF protein, named NF242, that can mitigate the toxic effects of the ALS-causing protein. The researchers discovered that when the two proteins interact with each other, the toxicity of the ALS-causing protein is removed, significantly reducing damage to the nerve cell and preventing its death.

In fruit flies, the approach notably extended lifespan, improved motor functions and protected nerve cells from degeneration. Similarly, in mouse models, the approach led to enhanced lifespan and mobility, along with a reduction in neuroinflammation markers.

“The investment – and foresight – of the Temerty Foundation has accelerated progress in finding an effective treatment for ALS.” —Western President Alan Shepard

The team’s path to discovery was paved by the Temerty family’s long-standing investment in ALS research at Western – support Strong calls “truly transformational.” Now Strong and his team have set a goal to bring their potential treatment to human clinical trials in five years, a mission that is fueled by a new gift from the Temerty Foundation.

The foundation, established by James Temerty, founder of Northland Power Inc., and Louise Arcand Temerty, is investing $10 million over five years to power the next steps to bring this treatment to ALS patients.

“Finding an effective treatment for ALS would mean so much to people living with this terrible disease and to their loved ones,” said James Temerty. “Western is pushing the frontiers of ALS knowledge, and we are excited for the opportunity to contribute to the next phase of this groundbreaking research.”

The new gift by the Temerty Foundation brings the family’s total investment in neurodegenerative disease research at Western to $18 million.

“Dr. Strong's relentless dedication to his field is matched only by the Temerty family’s deep desire to make a difference for the thousands of people around the world diagnosed with this devastating disease,” said Western President Alan Shepard.  “The investment – and foresight – of the Temerty Foundation has accelerated progress in finding an effective treatment for ALS. We are grateful for the Temerty family’s commitment to life-changing research.”

“This is a pivotal moment in ALS research that could truly transform patient lives,” said Dr. John Yoo, dean at Schulich Medicine & Dentistry. “With Dr. Strong’s leadership, our continued investment in the best tools and technology and the visionary support of the Temerty Foundation, we are thrilled to be heralding in a new era of hope for patients with ALS.”

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Internet use statistically associated with higher wellbeing, finds new global Oxford study

Links between internet adoption and wellbeing are likely to be positive, despite popular concerns to the contrary, according to a major new international study from researchers at the Oxford Internet Institute, part of the University of Oxford.

The study encompassed more than two million participants psychological wellbeing from 2006-2021 across 168 countries, in relation to internet use and psychological well-being across 33,792 different statistical models and subsets of data, 84.9% of associations between internet connectivity and wellbeing were positive and statistically significant. 

The study analysed data from two million individuals aged 15 to 99 in 168 countries, including Latin America, Asia, and Africa and found internet access and use was consistently associated with positive wellbeing.   

Assistant Professor Matti Vuorre, Tilburg University and Research Associate, Oxford Internet Institute and Professor Andrew Przybylski, Oxford Internet Institute carried out the study to assess how technology relates to wellbeing in parts of the world that are rarely studied.

Professor Przybylski said: 'Whilst internet technologies and platforms and their potential psychological consequences remain debated, research to date has been inconclusive and of limited geographic and demographic scope. The overwhelming majority of studies have focused on the Global North and younger people thereby ignoring the fact that the penetration of the internet has been, and continues to be, a global phenomenon'. 

'We set out to address this gap by analysing how internet access, mobile internet access and active internet use might predict psychological wellbeing on a global level across the life stages. To our knowledge, no other research has directly grappled with these issues and addressed the worldwide scope of the debate.' 

The researchers studied eight indicators of well-being: life satisfaction, daily negative and positive experiences, two indices of social well-being, physical wellbeing, community wellbeing and experiences of purpose.   

Commenting on the findings, Professor Vuorre said, “We were surprised to find a positive correlation between well-being and internet use across the majority of the thousands of models we used for our analysis.”

Whilst the associations between internet access and use for the average country was very consistently positive, the researchers did find some variation by gender and wellbeing indicators: The researchers found that 4.9% of associations linking internet use and community well-being were negative, with most of those observed among young women aged 15-24yrs.

Whilst not identified by the researchers as a causal relation, the paper notes that this specific finding is consistent with previous reports of increased cyberbullying and more negative associations between social media use and depressive symptoms among young women. 

Adds Przybylski, 'Overall we found that average associations were consistent across internet adoption predictors and wellbeing outcomes, with those who had access to or actively used the internet reporting meaningfully greater wellbeing than those who did not'.

'We hope our findings bring some greater context to the screentime debate however further work is still needed in this important area.  We urge platform providers to share their detailed data on user behaviour with social scientists working in this field for transparent and independent scientific enquiry, to enable a more comprehensive understanding of internet technologies in our daily lives.' 

In the study, the researchers examined data from the Gallup World Poll, from 2,414,294 individuals from 168 countries, from 2006-2021.  The poll assessed well-being with face-to-face and phone surveys by local interviewers in the respondents’ native languages.  The researchers applied statistical modelling techniques to the data using wellbeing indicators to test the association between internet adoption and wellbeing outcomes. 

Watch the  American Psychological Association (APA) video  highlighting the key findings from the research.

Download the paper ‘ A multiverse analysis of the associations between internet use and well-being ’ published in the journal Technology, Mind and Behaviour, American Psychological Association.

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• Published: 08 March 2021

COVID-19 in early 2021: current status and looking forward

• Chengdi Wang 1   na1 ,
• Zhoufeng Wang 1   na1 ,
• Guangyu Wang   ORCID: orcid.org/0000-0003-1312-884X 2   na1 ,
• Johnson Yiu-Nam Lau 3 ,
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Signal Transduction and Targeted Therapy volume  6 , Article number:  114 ( 2021 ) Cite this article

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• Infectious diseases
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Since the first description of a coronavirus-related pneumonia outbreak in December 2019, the virus SARS-CoV-2 that causes the infection/disease (COVID-19) has evolved into a pandemic, and as of today, >100 million people globally in over 210 countries have been confirmed to have been infected and two million people have died of COVID-19. This brief review summarized what we have hitherto learned in the following areas: epidemiology, virology, and pathogenesis, diagnosis, use of artificial intelligence in assisting diagnosis, treatment, and vaccine development. As there are a number of parallel developments in each of these areas and some of the development and deployment were at unprecedented speed, we also provided some specific dates for certain development and milestones so that the readers can appreciate the timing of some of these critical events. Of note is the fact that there are diagnostics, antiviral drugs, and vaccines developed and approved by a regulatory within 1 year after the virus was discovered. As a number of developments were conducted in parallel, we also provided the specific dates of a number of critical events so that readers can appreciate the evolution of these research data and our understanding. The world is working together to combat this pandemic. This review also highlights the research and development directions in these areas that will evolve rapidly in the near future.

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Long COVID: major findings, mechanisms and recommendations

Mechanisms of SARS-CoV-2 entry into cells

Infectious disease in an era of global change

Introduction.

In December 2019, a novel pneumonia with a high potential of transmissibility between humans was first reported. As a number of the initially identified cases had visited a large seafood and live animal market, some investigators were prompted to have an unconfirmed suspicion that this might be the initial source of infection. 1 , 2 The Chinese Center for Disease Control and Prevention, along with other related institutions, quickly identified the pathogen as a new type of coronavirus. To ensure that the information is shared quickly across the world, the first viral sequence was deposited into GenBank and made public on 26 December 2019 (LR757995, LR757998).

World Health Organization (WHO) issued alerts on 30 December 2019 and on 30 January 2020, and declared this viral infection as a Public Health Emergency of International Concern. On 11 February 2020, the International Committee of Taxonomy of Viruses named this virus Severe Acute Respiratory Syndrome (SARS)-CoV-2 based on the phylogenetic relationship of the coronavirus that caused the SARS outbreak in 2003. On the same day, WHO announced COVID-19 as the name of this novel disease caused by this virus following the guidelines of the World Organization for Animal Health and the Food and Agricultural Organization of the United Nations.

As of 1 February 2021, 13–14 months after the first description of the virus, there are >100 million subjects globally (from more than 210 countries) with confirmed SARS-CoV-2 infection based on the molecular assay. More than 2 million deaths have been attributed to COVID-19. 3 This pandemic has posed a great menace to human physical and mental health and has dramatically impacted the daily life with psychosocial implications on a global scale. This brief review (with updates up to 9 February 2021) summarized our knowledge and advanced on epidemiology, virology and pathogenesis, disease diagnosis, use of artificial intelligence in assisting diagnosis, treatment, and vaccine development.

Epidemiology of SARS-CoV-2 infection and public health impact

At the initial phase of the COVID-19 outbreak, the linkage between newly identified patients and their recent visits to the Seafood Wholesale Market suggested a potentially zoonotic origin of the virus. 1 , 2 Although the original and intermediate animal hosts for SARS-CoV-2 have not yet been definitively determined, the phylogenetic proximity of the SARS-CoV-2 to the coronaviruses from bats suggested the possibility that this novel virus may be related to the coronavirus from bats.

In January 2020, there was strong clinical evidence confirming the human-to-human transmission of SARS-CoV-2. The relative high infectivity, upper respiratory mode of transmission (may also be an element of transmission by contact), the relatively long incubation period, and the long viral shedding period, together with the current global travel pattern, constitute all the key elements for this virus to evolve into a pandemic quickly. 1 , 2 , 4 , 5

Current evidence has indicated that SARS-CoV-2 could be transmitted through various routes. This is not surprising as the viral receptor is human angiotensin-converting enzyme 2 (hACE2), which is expressed in a wide range of cell types, including lung alveolar cells, endothelial cells, blood vessels, gastrointestinal, and liver cells. As hACE2 is an essential gene, the entire human population is susceptible to SAR-CoV-2. There is as yet no publication that any genetic polymorphism of hACE2 is associated with resistance to SARS-CoV-2 infection. At present, a number of studies confirmed the transmission of SARS-CoV-2 through respiratory droplet transmission. 6 , 7 There is also strong evidence that physical contact with infected subjects or contaminated items can transmit this virus. 8 Healthcare workers taking care of screening for COVID-19 subjects and family members of COVID-19-infected subjects are at high risk of being infected. 9 As the gastrointestinal tract is also an infected organ, and there are reports of SARS-CoV-2 detected in feces, 10 it is possible that fecal–oral transmission can occur. There is also a report showing that SARS-CoV-2 can infect conjunctiva cells, suggesting that this can be another route of transmission. 11 Whether maternal–fetal transmission can occur remains to be established. 12

The public health impact of the SARS-CoV-2 pandemic is beyond everybody’s imagination. This pandemic has affected more than 210 countries and a majority of these countries are still under some infection control measures, including quarantine, lockdown, and recommended or mandatory general facemask use, and social distancing in public areas. As of 1 February 2021, >100 million people have been confirmed to have SARS-CoV-2 infection based on molecular assays that detect the viral nucleic acids (i.e., the virus). If one considers the number of subjects who were relatively asymptomatic or with mild symptoms and those that might not be tested for various reasons, the total number of subjects infected by SARS-CoV-2 is likely to be much >100 million. It is also important to note that >2 million have already died from SARS-CoV-2 infection (i.e., COVID-19).

A number of publications have described mathematical models trying to report and project the epidemiology of this infection. 10 , 13 , 14 , 15 , 16 Experiences were mainly based on data from the early affected countries. We have also established a four-compartment model and took into consideration both social interaction factors and viral transmissibility factors. 16 When the model was applied to data from Italy, UK, and the USA, it was estimated that the infection likely started in these places at around the same time, which is not surprising given the high level of travelers among epidemic regions. The model was able to estimate the impact of various public policies on the cumulative number of infected cases. The sad news is that this model predicted that with the current effectiveness of the policies (not extremely effective), SARS-CoV-2 infection, without an effective drug treatment or an effective vaccine for general use, is likely to stay for quite a while, even becoming seasonal. Given the need for various governments to reopen their countries to balance the spread of their infection vs the psychosocial, mental, and economic impact, many strategies were also proposed including staged reopening with intensive monitoring of new cases. 16 , 17 Our model showed that this measure may work if there are significant social distancing and partial lockdown in conjunction with general facemask use, and intensive monitoring for new cases to avoid a relockdown. 16 When we reviewed the various policies implemented in different countries, the compliance of the local population in the past 12 months, and the country’s infection rate, most of the outcome were in line with the predictions generated by the mathematical model.

Clinical features

The initial clinical symptoms of COVID-19 are similar to all types of viral pneumonia, with varying degrees of severity. The incubation period of SARS-CoV-2 is generally between 3 and 7 days [US Center of Disease Control (CDC) estimated a 2–14 day range], with the shortest being 1 day and the vast majority within 2 weeks. A proportion of infected subjects may remain asymptomatic. Fever, cough, and shortness of breath were the first typical symptoms of COVID-19 pneumonia initially highlighted by CDC, and chills, muscle pain, sore throat, and new loss of taste of smell were later added to the list. 18 Some patients have headache and myalgia, and others might have diarrhea, suggesting the involvement of the gastrointestinal tract. Patients with severe symptoms usually experience chest tightness and dyspnea in ~7–10 days after the onset of symptoms, and a proportion will progress to develop acute respiratory distress syndrome, septic shock, metabolic acidosis, and coagulopathy. It is also worth noting that some severely ill patients initially have mild symptoms like low-grade fever and mild cough, but rapidly deteriorate. 19 The pathophysiology involved with this rapid progress in this subset of patients remains to be determined.

Among the subjects showing symptoms (the COVID-19 disease), ~80% of patients had a mild illness, 14% of patients showed severe illness, and 5% of patients developed critical illness requiring intensive care or mechanical ventilation assistance. 20 Elderly people and people with comorbidities such as chronic obstructive pulmonary disease, diabetes, hypertension, and heart disease have an increased risk of severe illness. Importantly, some of these patients also had mild symptoms initially and progressed rapidly later. 19 There was a suggestion that patients on ACE inhibitors are prone to have more severe disease due to the induction of a higher level of hACE2 expression, but this has not been confirmed.

From a clinical management perspective, it is challenging to correct hypoxia with mechanical ventilation in critically ill patients. Some clinicians suggested the possibility of pulmonary vasculature involvement leading to a mismatch of the ventilation/perfusion system as both the ventilation and perfusion were affected in the pathogenesis. This line of research is certainly worth pursuing as the understanding of the pathogenesis based on the clinical hints may improve the precision of clinical management strategies. 21

Based on the latest information, most COVID-19 patients recovered, while a small subset of patients (from 0.5 to 5% depending on their access to proper treatment and preinfection health conditions) with severe illness will have severe/critical illness. 22

We have published the observation that in some recovered patients, the antibody titer dropped very quickly, which suggested that they may be susceptible to reinfection by SARS-CoV-2 again. 23 Along the same line, we described two patients in a cohort of 193 recovered patients who were diagnosed to have SARS-CoV-2 reinfection within 3 months of their first infection. 24 This observation was later observed by other investigators. 25 Reinfections hint that immunity against COVID-19 may be fragile and wane relatively quickly, with implications not just for the risks facing recovered patients, but also for how long future vaccines might protect people. There will certainly be more clinical data in the direction available in the near future.

Latest clinical data from China

As of 1 February 2021, among the 101,039 cases in China diagnosed with COVID-19, 93,726 patients recovered and 4826 patients died, with an overall case fatality rate of 4.8%. 3

The Chinese Center for Disease Control and Prevention published the epidemiological data of COVID-19 in China based on an earlier dataset. 20 Of the 72,314 “suspected” COVID-19 cases reported in mainland China, 44,672 (61.8%) were diagnosed to have COVID-19. Among the “suspected” and confirmed COVID-19 subjects, only 889 (1.2%) were asymptomatic. It is important to note that the denominator of this survey was based on suspected cases, that is, those with symptoms or closed contacts, and therefore, the total percentage of asymptomatic cases in reality can be much higher. The majority of the confirmed patients was between 30 and 79 years old (86.6%), and ~51% of these patients are male. In this cohort, there were 1023 deaths among the confirmed cases with a crude mortality rate of 2.3%, a male mortality rate of 2.8%, and a female mortality rate of 1.7%. The crude mortality rate in the ≥80-year-old age patients was 14.8%, and the critical case mortality rate in critical cases was 49%. The crude mortality rate of patients with unreported comorbidities was ~0.9%, and the mortality rate of patients with comorbidities was much higher: 10.5% for patients with cardiovascular diseases (with no information yet on whether these patients were ACE inhibitor takers), 7.3% for patients with diabetes, 6.3% for patients with chronic respiratory diseases, 6.0% for patients with hypertension, and 5.6% for patients with cancer. In another study in which the estimation was adjusted for censoring, demography, and missing data, the fatality rate was 1.38% for COVID-19, 13.4% for patients ≥80 years old, 6.4% for patients ≥60 years old, and 0.32% for patients <60 years old. Patients aged 0–9 years old had the lowest fatality rate of 0.003% among all age groups. 26

In China, most if not all of the children with SARS-CoV-2 infection had traceable history to either family members or recent contact with infected individuals. 27 , 28 Children usually had mild symptoms. In a series of 2143 cases of Chinese pediatric patients (median age: 7 years), >90% of children were asymptomatic or with mild-to-moderate disease. 29 Compared with adult patients, infected kids were less likely to have fever (children: 36%; adults: 86%), cough (children: 19%; adults 62%), and severe disease, including pneumonia (children: 53%; adults: 95%), elevated C-reactive protein (children: 3%; adults: 49%), and other severe disease types (children: 0%; adults: 23%). 13

The major cause of death in COVID-19 patients is respiratory failure. 30 , 31 In a retrospective study of 113 deceased patients, older people, male, patients with hypertension or other cardiovascular comorbidities (and with signs of myocardial damage), patients with hypoxemia-related symptoms, and patients with multiple organ dysfunction were at a higher risk to develop respiratory failure and die than others. 14

Clinical parameters during hospitalization, which might be associated with high fatality, include markers of significant inflammation like leukocytosis, lymphopenia, elevated C-reactive protein levels, and elevated lactic dehydrogenase levels, as well as the appearance of clinical complications. 32 In a retrospective study of 52 severely ill patients, 61.5% died within 28 days since diagnosis, and the median survival time of patients, from entering intensive care unit (ICU) to death, was 7 days. Nonsurvivors are mostly older patients (>65 years old) who usually have comorbidities. 33 In another retrospective analysis of 78 patients, factors related to disease progression and poor prognosis included advancing age, history of smoking, high maximum body temperature at admission, evidence of respiratory failure, significant reductions in serum albumin levels, and elevated C-reactive protein levels. 34 Thrombocytopenia was reported to be associated with severe illness and death, and also related to the development of disseminated intravascular coagulation (DIC). 35 Other factors related to poor prognosis include a high Sequential Organ Failure Assessment scores and d -dimer levels >1 μg/L (a marker of DIC), another marker of coagulation system involvement. Importantly, these severely ill patients continued to be infectious, shedding virus till they died, highlighting the infection risk to the medical professionals. 2

To predict the outcome of COVID-19 is of vital clinical importance to better allocate medical resources and provide individualized treatment for patients. The availability of clinical characteristics and parameters with potential prognostic implications will be of value in this respect and a number of institutions are conducting research in this direction.

Latest data from other countries

In the United States, the epidemiology data are evolving rapidly. By the end of 2020, there were 19.66 million confirmed SAR-CoV-2 infection with >340,000 deaths. 36 The State of New York conducted a serology test for antibodies to SARS-CoV-2 and found that 14–20% of New York City citizens (transit workers: 14.2%; citywide test: 19.9%) were positive, compared to ~3% in other parts of the State, with an overall ~12% of the tested subjects being seropositive for antibodies to SARS-CoV-2 (information released from New York Governor and New York City Mayor Office). Due to the fact that the results of the serology tests cannot be viewed alone without the other clinical and molecular assay data, the prevalence of COVID-19 in the New York State might even be underestimated. In the USA, the relationship between the fatality rate of the COVID-19 disease and age is well established. COVID-19 patients ≥85 years old have the highest fatality rate (10–27%), followed by 65–84 years old (3–11%), 55–64 years old (1–3%), and 20–54 years old (<1%), and ≤19 years old (<0.1%). Patients aged ≥65 years old account for 80% of deaths in the USA. Among the patients admitted to the ICU, 7% were patients ≥85 years old, 46% were 65–84 years old, 36% were 45–64 years old, and 12% were 20–44 years old, again confirming that seniors were the most vulnerable. 37 As was reported in a hospital in Washington State, the mortality rate of critically ill patients in the ICU was 67% and most of them had underlying diseases, typically congestive heart failure and chronic kidney disease. In the same geographic region, the fatality rate of COVID-19-infected residents in a long-term care facility in Washington was 34%. 38 , 39

Europe is also impacted substantially. As of today, Spain, Italy, UK, France, Germany, and Turkey all had >2.5 million confirmed infections (and they are all in the top 10 countries with the highest number of infected subjects) and with a mortality rate of 310 to 1606 per million. Russia and Iran also had a large number of infections, with 3.9 and 1.4 million confirmed infections and a mortality rate of 512 and 688 per million population, respectively.

In Latin America, Brazil at present has 9 million confirmed infections and a mortality rate of 1066 per million.

The overall fatality rate of COVID-19 appears to be lower (about 2%) than that of SARS (estimated to be 10%) and Middle East Respiratory Syndrome (MERS) (estimated to be 37%). 1 Despite the lower fatality rate, the high infection rate had driven COVID-19 to more fatalities than the total of SARS and MERS combined. 40

Outbreak prediction and preventive measures

As mentioned above, several research teams have modeled the epidemiological data to forecast the potential spread of SARS-CoV-2 infections either locally or globally. 15 , 16 , 41 Effective communications and collaborations among various countries have allowed testing and validating various hypotheses. Importantly, some control measures were implemented by various governments and their impact was assessed via population infection kinetics.

We have established a four-compartment model to determine the impact of various control and mitigation measures, including quarantine, lockdown, social distancing, and the general use of facemask, on the kinetics of infection in a population by comparing data either before or after the implementation of these measures and also between countries when different measures were implemented. 17 , 42 , 43 , 44 This model considered both social interaction factors and viral transmissibility factors. 16 The social interaction factors include per capita contact rate and also the infection rate upon contact, which can be modified by public policies, including reducing the social contact, or per capita contact rate by quarantine, lockdown, and social distancing, and also reducing the infection rate upon contact per general use of facemask. When this model was first established, we assumed similar viral transmissibility across virus variants recognizing that any RNA virus is known to have significant genetic heterogenicity for their survival generated through the lack of proof-reading activities of the viral RNA-dependent RNA polymerase. Recently, some of the variants have been shown to have increased transmissibility and, therefore, further revision of the model is warranted. Based on the analyses of this earlier mathematical model, the impact of social interaction factors (in particular, the per capita contact rate and the infection rate per contact) can be affected by public policies and recommendations (e.g., lockdown, the general use of facemask) imposed on a population or global scale. As mentioned earlier, some of the most recently identified SARS-CoV-2 variants isolated from South Africa were shown to have a higher infectivity clinically. Molecular characterization showed that amino acid substitutions on the spike (binding to the host cell receptor) and other viral proteins may be responsible for this viral evolution, which will always be in the evolutionary direction to become more infective and replication efficient. The mathematical model will certainly need to be adjusted when the viral transmissibility and viral replication efficiency (which may potentially reflect viral load) data are available.

This new knowledge, together with our understanding of infection control, will certainly impact the decision process of the lockdown exit, the importance of continuous monitoring, and also the reimplementation of some of these policies when there is a second wave of infection. Our knowledge in public health, in particular, infection control and mitigation measures, and the infection modeling knowledge, has advanced substantially recently, and hopefully, this will better prepare us for any future epidemics/pandemics.

Virology and pathogenesis

The viral genomic organization has been published and we expect that more virology information will be available soon. It is important to note that SARS-CoV-2, like other RNA viruses, has substantial genetic variability due to the lack of proof-reading activities of viral RNA-dependent RNA polymerase, which from an evolutionary standpoint is critical for viral adaptation and its “survival.” A study by Forster showed three different genotypes of SARS-CoV-2 and with the type being considered to be ancestral type using a closely related bat coronavirus (with 96.2% homology) as the root. 45 The A and C types are found mainly outside China, whereas type B is the most common type in East Asia. Although the sampling bias, the assumption/method of rooting, and the use of median-joining network may represent challenges in their analyses and conclusions, the genetic variability and the important role of phylogenetic network/tree analyses in our further understanding of this virus is certain. More studies in the foreseeable future will provide better insight into the classification and evolution of this virus.

The genetic variability of RNA virus will pose clinical challenges. First, the variability of the amino acid sequences in the spike protein is for host cell receptor binding, and whether any of the genotypic variations can lead to “escape” of the humoral neutralizing effect in recovered patients or vaccinees will have a significant clinical impact (see the South African variant below). Second, the virus can also evolve to be more replication efficient. Third, some of the viral proteins may evolve into mediators that may prevent the host immune system from recognizing or attacking infected cells, thus allowing infected cells to escape from the host immune attack/elimination and to generate more viruses. Finally, when antiviral therapy targeting a viral protein is available, the virus may mutate and “escape” and develop drug resistance.

Studies have confirmed that the SARS-CoV-2 binds to the human host receptor, the hACE2, suggesting that it has a similar tissue tropism as the SARS virus. 46 , 47 As hACE2 is mostly expressed in type II alveolar (AT2) cells in lungs, endothelial cells in blood vessels, gastrointestinal epithelial cells, and hepatocytes, therefore, this explains the frequent incidence of pneumonia, the observation of vasculitic features, and also the detection of viral RNA and antigens in the feces. Previous studies based on single-cell RNA-sequencing data showed that hACE2 is expressed in the lung, heart, esophagus, gastrointestinal tract, liver, kidney, and bladder, consistent with the damages to these target organs observed in the SARS-CoV-2-infected patients. 48 The high-level hACE2 expression in type II alveolar cells may explain the rapid onset and severity of pneumonia in some COVID-19 patients. Smoking has been shown to increase the lung gene expression of hACE2. 49

Importantly, compared with SARS-CoV, the unique structural features of the SARS-CoV-2 spike protein receptor-binding domain (RBD, which enables SARS-CoV-2 to bind to the host cell receptor) provided a higher binding affinity towards hACE2. Furin protease cleavage sites were also found in the spike protein of SARS-CoV-2, which was not present in other SARS-like coronaviruses. 50 In other coronavirus infections, the spike protein was found to downregulate hACE2, leading to excessive accumulation of angiotensin-II toxicity, which in turn may contribute to the progression to acute respiratory distress syndrome and fulminant myocarditis. 51

Given the high level of genetic variability and virus adaptability, it will not be surprising that new SARS-CoV-2 variants will emerge upon selective pressure from either antiviral treatment of the host immune selective pressure triggered by either the infection or the newly approved vaccines. Since September 2020, there were three viral variants that have raised concerns. On 21 January 2021, the UK New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) issued a paper outlining the results from several preliminary analyses of B.1.1.7. 52 The variant, which is highly transmissible, was initially identified in the south of England in September 2020. It has since spread to dozens of countries around the world. Molecular characterization showed that it has 17 mutations with amino acid substitutions/deletions in its genome, including eight in the spike protein (including the deletion of amino acids 69–70, which is believed to lead to conformation changes of the spike protein), which forms the basis of a number of the COVID-19 vaccines. NERVTAG concluded that there was a “realistic possibility” that infection with B.1.1.7 is associated with an increased mortality, compared with infection with the parental virus. The group stressed that its assessment was based on limited preliminary data, and even if confirmed, the overall risk of death would still be low. Another extremely infectious variant, P.1, has been circulating in Brazil since mid-2020 and was believed to contribute to the surge of infections in the Brazilian Amazon. Recently, B.1.351 was identified in South Africa in late 2020 (with some samples dating back to October 2020) with a number of mutations similar to the UK variant, but does not contain the deletion of the amino acid 69/70), but with an amino acid substitution E484K, which may affect neutralization by some polyclonal and monoclonal antibodies. 53 , 54 So far, there is no evidence that this variant has any impact on disease activity. This virus has spread to many countries including the USA (as of today, six cases identified in three different States), UK, China, and others. With this profile, there is a concern that the infected subjects who recovered may be susceptible to another round of infection and also the currently developed vaccines may not be able to protect against this variant, which will have a major impact on the evolution of this pandemic. The latest on the impact of this variant on vaccine efficacy will be discussed later in the vaccine section.

In February 2020, the first completed autopsy report of a deceased COVID-19 patient was released. The results showed an extensive inflammatory reaction with deep airway and alveolar damage, which are very similar to the pathological features of SARS and MERS. Electron microscopy examination of autopsy specimens showed the existence of large numbers of viral particles in alveolar epithelial cells. Gross pathology showed varying degrees of atrophy on all the lung lobes, and the cut surface showed decreased lung air volume with various degrees of consolidation. No obvious secretion retention was found in the trachea and the main branches of the bronchus. In the same report, pathological findings of limited lung autopsy of other COVID-19 patients were also provided. Most patients’ lungs, especially the middle and lower lung lobes, were adhered to the chest wall, suggesting inflammation of the peripheral lung tissue leading to the formation of adhesions. Microscopically, the main pathological changes in the lung were the increased number of macrophages in the tissue, serous fibrinous exudation (which could show up as ground-glass appearance in chest CT scans), accompanied by hemorrhage in some of the alveolar cavities, diffuse alveolar lesion, alveolar degeneration, and pulmonary consolidation. In some patients, a small number of alveolar cavities showed hyaline formation, type II alveolar epithelium hyperplasia with a widening of the alveolar space to various degrees, and interstitial fibrosis with lymphocytic infiltrates. In the small airways (mainly bronchiole and terminal bronchiole), there was mucus retention, and some had mucus plugs. Importantly, many patients had secondary bacterial infections, as evidenced by neutrophil-dominant inflammatory cell infiltrates in some of the lesions. A few patients had secondary fungal infections, as evidenced by the existence of fungal hyphae and spores in the lesions. These descriptions are consistent with the pathological changes of other viral pneumonia, and this can be compounded by secondary bacterial and fungal infections. 22 , 55 These findings are critical for clinicians as they may need to consider covering the patients early with anti-infective and anti-fungal treatments once there are clinical suspicions of secondary infection in these patients.

In the early stage of infection, SARS-CoV-2 virus entering the targets cells, such as bronchial epithelial cells and AT2 cells, could induce a series of host immune response. Furthermore, inflammatory signaling molecules are released by infected cells and alveolar macrophages in addition to recruited monocytes, neutrophils, and T lymphocytes. In the advancing stage of infection, SARS-CoV-2 virus infects pulmonary capillary endothelial cells, triggering an influx of monocytes and neutrophils, killing T lymphocyte cells, and accentuating the inflammatory response. 56 As a consequence, thickened interstitium, hyaline membrane formation, pulmonary edema, and activation of coagulation contributing to microthrombus formation even pulmonary thrombus may develop and appear (Fig. 1 ). The development of viral sepsis, referred to as life-threatening organ dysfunction, may further lead to multiorgan failure.

Immunopathogenesis of coronavirus disease 2019 (COVID-19) in early and advanced stage

Diagnostics for COVID-19

The detection of the viral nucleic acid sequence by either real-time reverse-transcription polymerase chain reaction (RT-PCR) analysis using viral-specific primers, nucleic acid next-generation sequencing (NGS), or other molecular tools is currently the gold standard for diagnosing SARS-CoV-2 infection. The current targets of SARS-CoV-2 sequence detection include three conserved gene sequences in the viral genome including the open reading frame (ORF), nucleocapsid protein (N) gene, and envelope protein (E) gene. 57 The specimens for testing can be nasopharyngeal swabs, sputum, other lower respiratory tract secretions, blood, and feces. Yang et al. 58 studied the different types of specimens from the respiratory tract (nasal swabs, throat swabs, sputum, bronchoalveolar fluid) in COVID-19 patients to evaluate the diagnostic accuracy based on a molecular diagnostic assay approved by the Food and Drug Administration (FDA) of China and found that sputum had the highest accuracy followed by nasal swabs. Another study tested the feasibility of detecting SARS-CoV-2 nucleic acid sequence in saliva, and SARS-CoV-2 sequence was detected in 91.7% (11/12) of COVID-19 patients’ saliva. 59 Despite the high sensitivity of the RT-PCR assay, the type of sample collected, sample storage method, the time needed for transportation to viral RNA extraction, and the reagents used for extraction can all contribute to the variability of the detection sensitivity. On the other hand, assays that were contaminated by the viral sequence DNA amplimers generated from other samples could create false positivity given the molecular amplification involved in the diagnostic system. Therefore, a reliable one-step device at low cost and reasonable efficiency is urgently needed. Certainly, a rapid point-of-care assay that can diagnose COVID-19 and other viral and bacterial pneumonia at the same time will be a very useful tool going forward. It will be reasonable to assume that SARS-CoV-2 is here to stay and can concurrently infect an individual with other respiratory pathogens including influenza, parainfluenza, rhinovirus, and other viral and bacterial pathogens.

Serologic assays for the detection of viral antigens, as well as IgG and IgM antibodies against the viral antigens, have also been developed for SARS-CoV-2 infection. Obviously, the detection of SARS-COV-2 viral antigen will be more rapid and can be a point-of-care test, but the sensitivity will be lower than that of the molecular PCR-based assays.

In a study that evaluated the respiratory viral load and serum antibody response in patients with COVID-19, saliva virus load was the highest in the first week after the onset of symptoms, which then declined over time. Most patients develop antibody responses (both IgM and IgG) on/after 10 days of symptoms. 60 Serum antibody levels did not correlate with clinical activity. In a more recent study, we showed that IgG and IgM appeared at around the same time and with a specific serology assay. We also showed that there was a high proportion of people in China who had exposure to SARS-CoV-2-developed antibodies to the virus (up to 3.4%) but remained asymptomatic. 61 As this is a novel virus, assuming that the capture antigen only contains epitopes specific to this virus, the seroprevalence will be reflective of the cumulative attack rate of this virus in the first season. There are a large number of such assays manufactured by different companies, but concerns remain on the performance (i.e., specificity, sensitivity, accuracy, reproducibility) of these assays, on top of the timing of the collection of the samples in the course of infection for a particular subject. 22 , 62 , 63 , 64

One key question going forward is how long the antibody response will last in infected subjects or vaccinees. If the humoral response does not last long, there is a need for booster doses and this question can only be addressed when infected subjects and vaccinees are followed up both by serology and clinically.

Application of artificial intelligence (AI) and internet technologies

Ai-aided radiologic diagnosis/screening system for covid-19.

Computed tomography (CT) of the chest is now considered as the primary imaging method of COVID-19 pneumonia due to high accuracy. In a meta-analysis of 50,466 inpatients, up to 97% of COVID-19 patients had abnormal chest CT. 65 Some reports indicated that CT scan could identify COVID-19 earlier even when compared to SARS-CoV-2 viral RT-PCR test in some patients. 66 Also, chest CT imaging abnormalities can occur in patients with mild or no symptoms. 67 In CT scan, most patients showed multiple ground-glass shadows and infiltrating shadows on bilateral lobules and subsections, while in severe cases, pulmonary consolidation may occur. Atypical features seem to be more common late in the disease. 63 Since the outbreak of the virus, as the burden placed on radiologists to read radiographic images skyrocketed, AI was considered as a tool to assist radiologists in COVID-19 pneumonia diagnosis.

We and other colleagues have established AI systems for accurate diagnosis of COVID-19 pneumonia based on CT parameters through deep learning. 68 , 69 Using a large CT database from 3777 patients, we developed an AI system that can diagnose novel coronavirus pneumonia (NCP) and differentiate it from other common pneumonia (CP) and normal controls (Fig. 2 ). With the combination of image-based and quantifiable clinical parameters, they also analyzed the relationship between imaging features and clinical markers and provided an AI model in prognostic prediction on progression to critical illness.

Illustration of network architectures of the proposed AI diagnostic system for COVID-19

Obviously, with the sophisticated implementation procedures and high-cost chest CT scans are not suitable as a frontline tool. To develop a comprehensive system to help combate COVID-19, we are also trying to develop an AI system for chest X-ray as a fast, frontline screening tool for the diagnosis of viral pneumonia, conceivably even before viral molecular tests results are available. Preliminary results have been encouraging. This can be of utmost importance to public health in a pandemic situation as this is a first-line assessment available in most healthcare centers, requiring radiographers only, with a quick turn-around time.

In general, AI can be very useful in the screening and management of COVID-19, 70 including increasing the screening accuracy of suspected cases, predicting the survival of critically ill patients, providing an optimal treatment plan, and in the screening of antiviral drugs. AI-powered robotic systems can also perform tasks for disinfection and support social distancing that is usually performed by humans, and thus reducing exposure risks.

Application of mobile internet in healthcare

With the rapid development of wireless internet technology and the increasing number of mobile phone users, Mobile Health technology has emerged as a potential solution to healthcare delivery for people with chronic diseases.

An AI-based medical assistant system can provide online analytic assistance to hospitals and clinics in analyzing the patient’s history, symptoms, and signs, imaging, laboratory blood tests, and even correlate with the latest epidemiology data (e.g., latest prevalence of COVID-19 in the area and areas that the subjects have traveled to in the last month) in risk assessment and identify the suspected COVID-19 patients, thus providing decision-making reference for the healthcare providers. During the COVID-19 endemic in China, more than 190 public medical institutions and nearly 100 internet hospitals across China provided online free consultation services, this avoiding patient contact and direct hospital visits, and at the same time providing some routine patient care needs while avoiding the risk of nosocomial COVID-19 infection.

AI-assisted public health initiatives

Big data from phone records, travel records, and social media data can provide travel patterns and trajectories of patients with suspected infection, which can be used to track patient’s close contacts, and forecasting outbreaks.

The Allen Institute of AI, in collaboration with leading research institutions, has released an open research database with weekly updates on the COVID-19 to accelerate new research projects that need real-time data. 71 Information application platforms such as geographic information systems, mapping dashboard, and case-tracking applications can enable online real-time or near real-time monitoring of patient trajectories and social media response to disease spread. Based on population travel data prediction risk maps and the trajectories of super spreaders and close contacts, the platforms can reveal the temporal and spatial distribution of COVID-19, and have been shown to be a timely and effective monitoring tool to track outbreaks and recommend appropriate government responses. 72 The visual and interactive global epidemic map developed by the research team at Johns Hopkins University in the USA is currently the most widely used COVID-19 epidemic surveillance. 73

For the epidemiology data, COVID-19 data in China, USA, Canada, and Australia, are collected at the provincial/state level, while for other countries, data are collected at the country level. In China, the National Health Commission, in collaboration with industry, developed an “intimate contact measurement” application platform in February 2020, and through this tool, the public can check if they were/are in close contacts with known infected COVID-19 patients by entering their name and ID number. 70 Obviously, privacy issues may not allow this to be implemented in other countries.

Treatment of COVID-19

In response to this serious global pandemic, the world’s biomedical/pharmaceutical establishments were unleashing an unprecedented response to the finding of safe and effective treatment strategies for COVID-19. Within 1 year, an antiviral drug, Remdesivir, and monoclonal antibodies against SARS-CoV-2, including bamlanivimab, and also the combination use of casirivimab and imdevimab were approved by the United States FDA and other regulatory authorities under Emergency Use Authorization (EUA) for the treatment of COVID-19.

From a pathogenetic mechanism perspective, as the viral infection spread to the lungs quickly and the COVID-19 pneumonia lung damage appeared to be a consequence of the host’s immune response attacking the infected lung cells, some investigators considered the drastic immune reaction to the lung tissue having some resemblance to the cytokine storm syndrome observed either in the transplant setting or as an adverse event of the chimeric antigen receptor T cell (CAR-T) therapy. Therefore, current attempts in the design of new therapies are focused on either the viral infection with either known antivirals or known drugs found to have antiviral activity in cell culture experiments or cytokines with known antiviral effect including interferons, or the control of the immunopathogenesis using immunomodulators to allow the lungs a chance to recover. There are also investigators evaluating the role of Chinese herbal medicine, the use of passive immunotherapy using serum from convalescent patients with COVID-19 and the use of stem cells for lung cell regeneration.

Early efforts were focused on identifying existing drugs that might also show antiviral effect against SARS-CoV-2 replication. There were reports of a large number of known drugs that showed some antiviral activity against SARS-CoV-2, including chloroquine, ribavirin, interferons, lopinavir/ritonavir, and others.

As the first country to be affected by COVID-19 in a major way, most of the Chinese COVID-19 patients were on some type of clinical study protocol and such an approach has addressed clinically some of the early suggestions based on laboratory virus cell culture experiments. 1 , 74 , 75

Chloroquine, an old anti-malarial drug with high lipid solubility, is known for its pH-dependent antiviral effect including coronavirus. Hydroxychloroquine in combination with azithromycin was also getting attention initially based on a small single-arm pilot study in France showing a reduction of viral load during therapy. 76 Another study conducted in China ( n  = 62, patients with mild/moderate pneumonia) comparing hydroxychloroquine alone vs standard care at the time of the study also suggested a beneficial effect. 75 In contrast, there were also a number of reports from Spain, UK, and USA, showing the lack of clinical benefit of hydroxychloroquine and azithromycin in COVID-19 patients. 77 , 78 , 79 Also, this class of drugs is also known to induce QT prolongation and ventricular arrhythmia. Although there is no solid evidence that azithromycin treatment induces QT prolongation, there were reports of an excess of cardiovascular deaths associated with its usage (47 cardiovascular events per million completed courses of treatment) highlighting the potential risk involved. In fact, the American College of Cardiologists issued their opinion on 29 March 2020, suggesting that physicians should be aware of this potential complication. Given the clinical challenges, FDA issued an EUA on 28 March 2020 for the use of chloroquine and hydroxychloroquine in adults and adolescents for those for whom a clinical trial is not available or participation not feasible and required the mandatory reporting of adverse events to FDA Med-Watch. While controlled clinical studies were being conducted to evaluate the risk–benefit ratio of this treatment approach, FDA revoked the EUA on 15 June 2020, after they analysed the emerging scientific data, and determined that the legal criteria for issuing an EUA was no longer met. 80

Ribavirin, in combination with interferon, was also used in some of the early clinical studies. Ribavirin is a viral-static agent in the cell-based assay. It is both an RNA-dependent RNA polymerase inhibitor and a viral mutagen (the sugar moiety of ribavirin is a pentose with hydroxyl groups in both 2′ and 3′ position and will allow integration into the RNA), which may cause replication catastrophe for the virus despite replication. Therefore, its effect as monotherapy may only be revealed in terms of clinical outcome instead of reduction in viremia, as reflected in the chronic hepatitis C studies. In addition, ribavirin showed strong synergistic activities with interferon and was used in combination to treat hepatitis C, another single-stranded RNA virus, in the late 1990s. The combination of ribavirin and recombinant interferon has also been shown to have potent efficacy in inhibiting MERS-CoV replication, another coronavirus. 81 In the Chinese National Health Commission new coronavirus infection pneumonia diagnosis and treatment plan (trial version 7), one of the recommendations was to consider the use of intravenous ribavirin in combination with inhaled interferon-beta-1b as a possible treatment option for further evaluation. 82 A prospective, controlled, multicenter clinical study (ChiCTR2000030922) of long-acting interferon plus ribavirin to treat COVID-19 was currently conducted in China to evaluate its clinical efficacy and safety.

Lopinavir–ritonavir was initially identified to have micromolecular IC-50 activity against SARS-CoV-2 in in vitro testing, offering hopes for clinical activities for this anti-HIV protease drug combination based on drug repurposing. A recent publication based on a randomized controlled study in 199 COVID-19 patients showed that the combination of lopinavir–ritonavir offered no clinical benefit in adult patients with severe COVID-19. 83 In another published phase II study, triple combination treatment consisting of interferon-beta-1b, ribavirin, and lopinovir–ritonovir was compared with lopinovir–ritonovir alone (control arm) and showed safety and superior efficacy in alleviating symptoms and shortening the duration of viral shielding and hospital stay in patients with mild-to-moderate COVID-19 (ClinicalTRials.gov: NCT04276688).

Remdesivir is a potent RNA-dependent RNA polymerase inhibitor initially developed for the Ebola and Marburg viruses, which was found to have a good effect against respiratory syncytial virus, Junin virus, Lassa Fever virus, and coronaviruses, including SARS and MERS, and has recently also been shown to have good inhibitory activity against SARS-CoV-2. It is a prodrug of an adenosine analog given intravenously. Early clinical experience in the US showed that remdesivir is effective in reducing the SARS-CoV-2 viral load without significant adverse events. In China, two clinical trials are currently conducted to evaluate the efficacy of remdesivir in COVID-19 patients with the mild-to-moderate disease (NCT04252664) and severe critically ill patients (NCT04257656). In the initial series of 12 US patients with COVID-19 in the USA, the CDC reported that three patients received remdesivir as part of the expanded access program and noted gastrointestinal side effects and elevated liver enzymes in these patients, highlighting the importance of addressing both clinical efficacy and potential adverse events in the currently ongoing phase III studies. 84 Another phase III study on the use of remdesivir in hospitalized patients with COVID-19 who received remdesivir had a 31% faster time to recovery than those who received placebo ( p  < 0.001). Specifically, the median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir vs 11.6% for the placebo group ( p  = 0.059). This drug received FDA EUA for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe diseases 2 days after the data were available. Based on the same dataset, remdesivir was also approved in Japan via an exceptional approval pathway 8 days later.

Another board-spectrum antiviral, umifenovir, which inhibits membrane fusion of the virus to the host cells and registered for use on the influenza indications in Russia, was also found to have an effect against SARS-CoV-2 in virus cell culture assay. A multicenter randomized controlled trial (ChiCTR2000029573) is underway to evaluate the efficacy of umifenovir in combination with lopinavir/ritonavir vs the three drugs together with interferon.

Passive immunotherapy using plasma from COVID-19 convalescent patients were also evaluated early on as a treatment option. A small pilot study (5 patients) in China showed that after receiving passive immunotherapy plasma, the patient’s viral load decreased rapidly, and the patient’s clinical symptoms improved, highlighting the viral neutralizing activities in the convalescent patients’ plasma. 85 On 27 March 2020, Houston Methodist Hospital announced that they have obtained an emergency investigational new drug application to evaluate this convalescent plasma therapy in critically ill COVID-19 patients in the USA. Although this approach may have some scientific merits, the potential adverse reactions of plasma therapy should not be overlooked. In addition, the standardization process in terms of the dose, treatment regimen, and its long-term impact on the recipient’s immune response development have not been established, which should be addressed in randomized clinical studies. 86

Along the same line, a number of pharmaceutical and biotech companies developed monoclonal antibodies against the spike protein of SARS-CoV-2, which contains the RBD that binds to the host cell receptor hACE2. The first antibody tested was bamlanivimab (LY-CoV555). In a phase 2 study, studying three doses of the drug vs placebo (465 patients in four arms) in patients with mild-to-moderate COVID-19 and within 10 days of symptom onset, there was a reduction in the nasopharyngeal SARS-CoV-2 level with the high-dose group, and a reduction in pre-specified endpoint of COVID-19-related hospitalization, emergency department visit, or death (6.3% in placebo vs 1.6% overall for the three doses group). On 9 November 2020, FDA issued an EUA based on the phase 2 data. However, another study of the same antibody did not meet the primary endpoint for COVID-19 patients who were hospitalized. FDA did emphasize in their press release that this antibody was not authorized for hospitalized COVID-19 patients and that the use of this antibody might be associated with worse clinical outcomes in the hospitalized patients with COVID-19 requiring high-flow oxygen or mechanical ventilation. In a phase III study, another monoclonal antibody against SARS-CoV-2 spike protein epitope, etesevimab (LY-CoV016), was evaluated in combination with bamlanivimab, and on 26 January 2021, there was an announcement that in the 1035 patients with mild and moderate COVID-19 and within 10 days of symptom onset (non-hospitalized), this combination use of monoclonal antibodies resulted in a 70% reduction (7.0% in placebo vs 2.1% in treated group) in the pre-defined events (defined as COVID-19-related hospitalizations and deaths).

On 21 November 2020, 12 days after the EUA of bamlanivimab was issued, FDA also issued an EUA for casirivimab and imdevimab (REGN10933 and REGN10987), two monoclonal antibodies recognizing two different epitopes on the SARS-CoV-2 spike protein RBD. This authorization was based on a phase 2 study involving 799 non-hospitalized adult patients with mild-to-moderate COVID-19 symptoms, and similar endpoint results as bamlanivimab were achieved. On 29 December 2020, encouraging initial results (that passed the futility analysis) were also announced for the use of this antibody cocktail in hospitalized patients on low-flow oxygen. The immune status of patients on entering the trial was a strong predictor of viral load and outcome. Patients seronegative for antibody against SARS-CoV-2 had significant viral load drop and passed the futility test for lower risk of death or requiring mechanical ventilation (~50% reduction), based on an interim post hoc analysis. This study is still ongoing.

Another approach is to prevent severe lung disease development related to the host immune attack. Alveolar lavage fluid from COVID-19 patients based on single-cell sequencing technology showed that macrophages may play an important role in the pathogenesis of COVID-19. 87 Macrophages are important effector cells for interleukin-6 (IL-6). The elevated IL-6 also showed a similar profile as observed in bone marrow transplant patients and patients with cytokine storm syndrome after CAR-T therapy. Tocilizumab is a humanized IgG 1 monoclonal antibody that can specifically bind to soluble or membrane-bound IL-6 receptors and blocks the signaling pathways of both IL-6 and granulocyte–macrophage CSF (GM-CSF), and this reduces the systemic inflammatory response. 88 A multicenter randomized controlled clinical study is already underway to evaluate the efficacy and safety of tocilizumab in the treatment of patients with moderate to severe and critical illness in China (registration number: ChiCTR2000029765). There are studies ongoing in other countries as well. On 3 February 2021, FDA issued a treatment guideline on tocilizumab and other IL-6 inhibitors. The panel summarized that initial studies evaluating the use of IL-6 inhibitors for the treatment of COVID-19 produced conflicting results. Many trials were limited by low statistical power, heterogeneous study populations with varying degree of disease severity, and/or low frequency of concomitant use of corticosteroids, which has become the standard of care in patients with severe or critical COVID-19. Based on available information, the FDA panel determined that (a) for patients who are within 24 h of admission to the ICU or who require invasive or noninvasive mechanical ventilation or high-flow oxygen (>0.4 FiO 2 /30 L/min of oxygen flow), there are insufficient data to recommend either for or against the use of tocilizumab (or sarilumab, which is also an anti-IL-6) for the treatment of COVID-19, and (b) for patients who do not require ICU-level care or who are admitted to the ICU but do not meet the critical need listed in (a), tocilizumab or sarilumab should not be used apart from a clinical trial setting. 89

There are also other investigators who are evaluating other immunomodulatory approaches, including antibody against CCR5, antibody against GM-CSF, antibody against vascular endothelial growth factor, and immunostimulants anti-PD1 and thymosin. No date from any large clinical studies on these modalities is currently available.

Along the same line, it will be tempting for investigators to evaluate the effect of glucocorticoids in COVID-19 patients to reduce the excessive host immune attack against the SARS-COV-2-infected cells. However, one should also note that steroids may impact the immune system and reduce the host immune response against the virus with the induced immunosuppression. In addition, steroids like dexamethasone tend to increase clotting factor and fibrinogen concentrations, and in a procoagulant state in severe COVID-19, there is the potential that steroid use may also induce damages. 90 On 17 July 2020, the preliminary report of an open-label study on the use of dexamethasone in 6425 hospitalized patients (2104 on dexamethasone plus the standard care, 4321 on usual care) with COVID-19 showed that the incidence of death was lower among patients receiving invasive mechanical ventilation (29.3% in the dexamethasone group vs 41.4% usual care group) and also patients receiving oxygen without invasive mechanical ventilation (23.3 vs 26.2%) in the dexamethasone-treated group. 91 The beneficial effect was not seen in patients who were not receiving respiratory support. As of today, the use of dexamethasone 6 mg for up to 10 days in hospitalized COVID-19 patients is recommended. In China, the current practice is that glucocorticoids should only be considered if the following four conditions are met: (1) adults (age ≥18 years); (2) SARS-CoV-2 infection confirmed by PCR or serum antibodies against the virus; (3) symptoms (including fever, cough or other related infection symptoms) occurred within 10 days, with radiologically confirmed pneumonia and with rapid progress; and (4) the patient’s blood oxygen saturation is ≤93% or significant shortness of breath (breath rate ≥30 breaths/min) or with PaO 2  ≤ 300 mm Hg. In addition, the use of glucocorticoids should follow the principle of “low dose with a short course” 88 and the aim of using the steroids to reduce the edematous component that impedes patient’s oxygenation. A randomized controlled study (ChiCTR2000029386) based on the above principles evaluating the efficacy and safety of glucocorticoid therapy in severe COVID-19 with low tissue oxygenation is ongoing in China.

In China, stem cell therapy was also evaluated in patients with severe/critical COVID-19. The principle is to provide fresh stem cells to assist the various organs, in particular the lung, to have a better chance to recover. 32 At the time of writing of this report, there are 22 COVID-19 stem cell therapy clinical studies registered in the Chinese Clinical Trial Registry.

With regards to the general supportive care for these patients, there are four major areas for attention based on all the clinical reports and our personal experiences. The most important is the pulmonary function support. Pneumonia is the most common feature of severe COVID-19. 92 For mild-to-moderately severe COVID-19 patients with hypoxemia, supplemental oxygen therapy, including high-flow nasal catheter oxygen therapy should be used when needed. For severe/critically ill patients with respiratory distress, noninvasive or invasive mechanical ventilation, or even extracorporeal membrane oxygenation should be considered. 93 , 94 The second is the support of the renal function. Three clinical studies have indicated that the proportion of patients receiving continuous renal replacement therapies (CRRT, i.e., dialysis) is moderate-to-severe COVID-19 patients was 7–9%. In the ICU settings, CRRT was usually required in 5.6–23.0% of all patients. 95 , 96 , 97 The third aspect is the coagulation profile. With rapid tissue damage induced by the virus, an abnormal coagulation profile suggestive of low-grade DIC is common and was observed in ~20% of all COVID-19 patients, and in nearly all severe/critically ill patients. 88 A study is ongoing to evaluate the efficacy and safety of enoxaparin sodium in the treatment of coagulation disorders in hospitalized COVID-19 patients (ChiCTR2000030701). Finally, bacterial and fungal secondary infection is another important factor to consider. In a study of 99 patients with COVID-19, one patient had Klebsiella pneumonia , Acinetobacter baumannii , and Aspergillus flavus detected simultaneously and repeatedly in the sputum culture. One patient had Candida glabrata and three patients had Candida albicans secondary infection. 75 Therefore, it is essential to watch out for secondary infection in the presence of COVID-19 pneumonia.

SARS-CoV-2 vaccine development

A considerable number of SARS-CoV-2 preventive vaccine projects were initiated shortly after the reporting of this virus, including technologies that generate inactivated virus vaccine, viral protein subunits vaccine, messenger RNA (mRNA) vaccine, DNA plasmid vaccine, and recombinant human adenovirus type 5 (rAd5) or simian adenovirus type 26 (rAd26) expressing SARS-COV-2 spike protein, non-viral replicating vector expressing SARS-CoV-2 protein vaccine, and also replicating viral vector expressing SARS-CoV-2 protein vaccine. So far, there have been at least 30 announced vaccine projects globally, and vaccines derived from mRNA, expression using recombinant adenoviral vectors, and inactivated virus have already gained regulatory approvals in certain countries. 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 The major COVID-19 candidate vaccine platforms were listed in Table 1 .

To conduct experiments with SARS-CoV-2 requires a laboratory environment of at least Biosafety level 3. The use of mRNA in a vaccine is innovative and relatively safe. As it is synthetic, the path of product development will be much faster. Traditionally, a vaccine will take 10–15 years to be confirmed safe and commercially mature. But in such a pandemic context, the public and governments demand that an effective preventive vaccine be available as soon as possible. Regulatory authorities have also expressed their willingness to expedite the regulatory review process under the EUA path.

mRNA vaccines

The first two vaccines that advanced quickly to clinical studies were based on the mRNA technology.

The first mRNA COVID-19 vaccine was received by FDA EUA on 10 December 2020. Based on an efficacy trial involving 44,000 volunteers, only eight people who got two shots of the vaccine spaced 21 days apart developed the disease, as compared with 162 participants in the placebo group, giving a COVID-19 disease efficacy of 95%. Severe disease occurred in nine placebo recipients, but in only one vaccine recipient there was a temporary need for oxygen and was not hospitalized. This vaccine, named Pfizer-BioNTech COVID-19 vaccine (BNT162b2), has been approved by health agencies for application in subjects 16 years or older. 106 The challenge is that this vaccine needs to be stored at −80 °C during transportation, which is hard to achieve during the delivery and distribution.

The second mRNA COVID-19 vaccine (mRNA-1273) was approved by FDA EUA a week later on 18 December 2020. 107 The efficacy trial was conducted based on ~30,000 volunteers, resulting in an efficacy of 94% with 11 volunteers in the vaccine group and 185 subjects in the placebo group developing COVID-19. Severe COVID-19 illness occurred in 30 recipients in the placebo group and only one in the vaccine group. This vaccine has been approved for those aged 18 years and older; the standard for the storage condition of this vaccine is −20 °C.

For both the aforementioned vaccines, FDA requested the developers to prepare a long-term plan of follow-up in pharmacovigilance on a public scale to complete the safety profile, while acknowledging the effectiveness of both vaccines in preventing symptomatic COVID-19 disease occurrence. There are no data available yet as to whether the mRNA vaccine also prevents infection. In a survey in Israel, the Israeli Ministry of Health 108 reported that of the 750,000 fully vaccinated people over 60 years old, only 531 (0.07%) were tested positive for COVID-19 so far, and 38 were hospitalized, with symptoms ranging from moderate to critical. Most experts believe that a proportion of the vaccinees may still get COVID-19 and be likely to spread the virus. Therefore, we should still recommend the vaccinees to use a facemask and observe social distancing. Despite these limitations/cautions, the benefits of the mRNA vaccines are significant and outweigh the concerns, and they have been approved in a number of countries already. 109 , 110

With the recent identification of a viral variant in South Africa, in which its mutation in spike protein (E484K) was found to affect neutralization by some polyclonal and monoclonal antibodies, there was a concern as to whether these early mRNA vaccines will still be effective. Both companies have tested this question in laboratory studies. The sera from vaccines for both the mRNA vaccines were found to still be effective in neutralizing the variant, but with less activity compared to the wild-type SARS-CoV-2 virus. The studies have not been peer-reviewed. As these are synthetic mRNA vaccines and can be adjusted for the variant sequence quickly, they are planning to develop a new vaccine targeting the South African variant for further testing.

Recombinant adenoviral vectors expressing SARS-CoV-2 spike protein/RBD

A number of other institutions/companies in China, UK, Russia, and USA developed recombinant adenoviral vector expressing the COVID-19 genes as vaccines. China has a version based on the human adenovirus vector (rAd5 backbone). United Kingdom (Oxford University) has a version (code name AZD1222) that is based on a simian adenoviral vector. A multinational company also has a similar vaccine based on Ad26 backbone (code name Ad.26.CoV2.S or JNJ-78436725), which have data suggesting that one dose may be enough. Russia has a COVID-19 vaccine (code name Sputnik V) that uses two recombinant adenovirus backbone, with one dose using the rAd5 and the other dose using the rAd26 to reduce the interference by the host immunity against the vector backbone. The China group published their first set of clinical data on 15 August 2020. 98 In this phase 2 trial, the vaccine was found to induce significant immune responses in the majority of the recipients after a single immunization. No data from their phase 3 study are available at the time that this review was prepared.

The clinical study data on AZD1222 vaccine (formerly known as ChAdOx1) was published on 19 December 2020 and 9 January 2021. 111 , 112 Overall, the vaccine has an acceptable safety profile, well tolerated in older adults, has similar immunogenicity across all ages, and effective against symptomatic COVID-19 in the interim analysis. However, an error in dosing where nearly 3000 participants were given half dose in their first vaccination and full dose in their second vaccination led to better protection at 90%, compared to those who received two full doses and had protection at 63% (overall at 70%). The reason why a lower dose produced a more robust immune response remains to be determined, but it is possible that the lower first dose may induce less host immune response to the vector so that the second dose may be more effective in inducing a better response. This vaccine has already been approved in the UK. The vaccine developer is now conducting a study on 30,000 subjects in the USA and may submit for FDA approval in the second quarter of 2021. Just before we submitted this review, this vaccine was reported to be less effective for the South African variant. For the South African trial of the vaccine, conducted in ~2000 people, the efficacy against the mild and moderate disease was reported to be ~22%, and this would not meet the minimum international standards for emergency use. Data are not yet peer-reviewed.

China reported the first rAd5-based COVID-19 vaccine on 29 February 2020, ~2 months after the viral genome was reported, in a news release with a video showing them receiving the vaccine (code name Ad5-nCoV). They reported their phase 1/2 data on 22 May 2020 (and paper published on 13 June 2020), showing that the vaccine was safe and a single dose was able to trigger both humoral and cellular immune response in a dose-response fashion. 113 On the day before we submitted this review (8 February 2021), their phase 3 study in Pakistan was announced, and an overall protection efficiency of COVID-19 was 75% and the protection of severe/critical COVID-19 was 100%. They also claimed on 1 February 2021 that the overall response rate for their phase 3 study conducted in five countries with 40,000 people showed an overall protection efficiency of 66% and a protection against severe/critical COVID-19 to be 91%. 114 Note that these response rates were generated with only one dose of the Ad-nCoV vaccine. There is no data yet on the effect of this vaccine against the South Africa SARS-CoV-2 variant.

The Russian heterologous COVID-19 vaccine (rAd26 and rAd5-based) was shown in a phase 1 trial to induce a good humoral and cellular immune response and was also found to be safe in a report published on 26 September 2020. 99 On 2 February 2021, the phase 3 study interim data on 20,000 subjects were reported. From 21 days after the first dose of vaccine (the day of dose 2), 16 subjects (0.1%) from the vaccine group and 62 subjects (1.3%) from the placebo group were confirmed to have COVID-19, giving a vaccine efficacy of 92% in protection against COVID-19 disease. 115 The vaccine was well tolerated. Note that the Russian health authority has already approved this vaccine with the phase 2 data on 11 August 2020.

The rAd.26.CoV.2.S/JNJ-78436725 vaccine has had their phase 3 data released in a press release on 29 January 2021. The vaccine, which requires only a single injection (as claimed by the company), can also be stored in a refrigerator for months. The interim analysis assessed 468 cases of symptomatic COVID-19 among 44,325 adult volunteers and the investigational vaccine was 66% effective at preventing the study’s combined endpoints of moderate and severe COVID-19 at 28 days post vaccination among all volunteers, including those infected with an emerging viral variant. They also claimed that it is 85% effective in preventing severe COVID-19. FDA recently announced that there will be an advisory meeting to discuss the request for EUA for their vaccine on 26 February 2021. Recently, the company also reported that the protection against mild disease in South African was weaker, at 57%.

Inactivated virus vaccine

For inactivated vaccines based on the more traditional vaccine manufacturing methods, results of a phase 1/2 trial on BBIBP-CorV were published on 1 January 2021, demonstrating a good safety profile and the identification of the dose for phase 3 development. On 31 December 2020, the Chinese health authority announced that this vaccine was granted conditional marketing authorization based on the interim analysis of its phase 3 trial, which showed 79% efficacy against COVID-19. 116 Another company was developing a COVID vaccine based on a similar approach (code name CoronaVac) and published their phase 1/2 clinical trial on 3 February 2021; the vaccine was found to be safe, but the selection of a dose was needed for confirmatory studies. 117 A third institution is also developing an inactivated COVID-19 vaccine. 101 Again, in a publication on 13 August 2020 on the data of their phase 1/2 studies, they had shown that their inactivated vaccine was safe and immunogenic. Phase 3 data for all these vaccines are not yet available.

There are also other companies in different countries trying to develop inactivated vaccines and to combine this with different adjuvants that may further boost its efficacy.

Recombinant viral protein vaccines

Another approach is to use recombinant viral protein as a vaccine. One of the companies is using recombinant spike protein nanoparticle vaccine (code name NVX-CoV2373, which composed of a trimeric full-length spike glycoprotein and their Matrix-M1 adjuvant). On 2 September 2020, the phase 1/2 trial data were published. 118 The data showed that this vaccine appeared to be safe, and it elicited an immune response that exceeded levels in COVID-19 convalescent serum. On 28 January 2021, the company announced that their vaccine demonstrated nearly 90% efficacy against COVID-19, in a cohort where half the cases were due to the new UK variant. However, in a trial in South Africa, the overall vaccine efficacy was 49% largely due to the South African variant. In addition, findings from that study suggested that prior infection with the wild-type strain may not fully protect against new infection from the variant strain. The company announced that regulators from the USA, UK, Canada, and Europe had begun to review these data in a rolling submission process.

Also, along the line of using recombinant viral glycoprotein, Yang et al. 119 described that a vaccine targeting the RBD of the spike protein can induce protective immunity. What was important is this study was the observation that the immunogenicity of the RBD domain is stronger than the entire spike protein. Also, this study defined the importance of vaccine adjuvant in the potential use of RBD glycoprotein in eliciting a better host immune response in animals. Phase 1 and 2 studies are currently ongoing (ChiCTR20000037518 and ChiCTR20000039994).

Forward looking

It is important to note the following forward-looking points. First, similar to the mRNA vaccines, it is likely that the other vaccines are also effective in protecting against the COVID-19 disease but not the infection, and if this is the case, vaccinees can still be infected and help to spread the virus around. Use of facemask and social distancing will still be required to support the world to control this pandemic. Second, how long will immunity last after the vaccination? Do we need booster doses from time to time? The vaccinees will need to be followed up to address this question. The same question can be related to COVID-19-recovered patients: Do COVID-19-recovered patients need to receive COVID-19 vaccine? The CDC recommended that, based on the rapid reduction in serum-neutralizing antibodies in some recovered patients, they are recommending that COVID-19 patients should also receive COVID-19 vaccine. 120 Third, SARS-CoV-2 is an RNA virus and this type of virus can easily mutate to “escape” the immune pressure. With regards to the immune selection, the current data suggest that the South African variant will represent a major challenge to the vaccine development for universal coverage of all SARS-CoV-2 variants. Even when new vaccine candidates are developed to tackle the South African viral variant, it is possible that there may be newer variant evolving and be revealed with additional immune pressure. We can expect an array of data in this direction in the next couple of years. A recent publication by Kemp et al. 121 also revealed the strong selection on SARS-CoV-2 during convalescent plasma therapy associated with the emergence of viral variants with the evidence of reduced susceptibility to neutralizing antibodies. The understanding of the interplay between the humoral response and the viral adaptation will be important for us to design a better vaccine and immunotherapy for COVID-19.

Conclusions

The COVID-19 pandemic has challenged the world not just in the global health but also the global psychosocial and economic health. This pandemic is testing our resolve to solve challenging situation together. The scientific world has taken on this challenge and is investigating this virus, the COVID-19 disease, and pathogenesis, and have developed systems in epidemiology, diagnosis, clinical management, and development of vaccines in a timeline that is unprecedented (all within 1 year). This brief summary tried to describe some of the development and also the unanswered questions, with an attempt to use this information to allow us to look forward. To all the unsung heroes who worked so far to help the world combat this pandemic, we would like to share this quote from Sir Isaac Newton:

If I have seen further, it is by standing upon the shoulders of giants.

Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395 , 497–506 (2020).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Zhou, F. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395 , 1054–1062 (2020).

World Health Organization. Coronavirus Disease (COVID-2019) Situation Reports (World Health Organization, 2020).

Li, Q. et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N. Engl. J. Med. 382 , 1199–1207 (2020).

Chan, J. F.-W. et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 395 , 514–523 (2020).

Holshue, M. L. et al. First case of 2019 Novel Coronavirus in the United States. N. Engl. J. Med. 382 , 929–936 (2020).

Anfinrud, P., Stadnytskyi, V., Bax, C. E. & Bax, A. Visualizing speech-generated oral fluid droplets with laser light scattering. N. Engl. J. Med. 382 , 2061–2063 (2020).

Article   PubMed   Google Scholar  

van Doremalen, N. et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N. Engl. J. Med. 382 , 1564–1567 (2020).

Huang, R., Xia, J., Chen, Y., Shan, C. & Wu, C. A family cluster of SARS-CoV-2 infection involving 11 patients in Nanjing, China. Lancet Infect. Dis. 20 , 534–535 (2020).

Xu, Y. et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat. Med. 26 , 502–505 (2020).

Article   CAS   PubMed   Google Scholar  

Hui, K. P. Y. et al. Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures. Lancet Respir. Med. https://doi.org/10.1016/s2213-2600(20)30193-4 (2020).

Chen, H. et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet 395 , 809–815 (2020).

Qiu, H. et al. Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study. Lancet Infect. Dis. https://doi.org/10.1016/S1473-3099(20)30198-5 (2020).

Chen, T. et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 368 , m1091 (2020).

Article   PubMed   PubMed Central   Google Scholar  

Giordano, G. A.-O. et al. Modelling the COVID-19 epidemic and implementation of population-wide interventions in Italy. Nat. Med. 26 , 855–860 (2020).

Wang, T. et al. A four-compartment model for the COVID-19 infection—implications on infection kinetics, control measures, and lockdown exit strategies. Precis. Clin. Med. 3 , 104–112 (2020).

Article   Google Scholar  

Gilbert, M., Dewatripont, M., Muraille, E., Platteau, J. P. & Goldman, M. Preparing for a responsible lockdown exit strategy. Nat. Med 26 , 643–644 (2020).

Centers for Disease Control and Prevention of USA (CDC). Symptoms of Coronavirus (COVID-19). https://www.cdc.gov/coronavirus/2019-ncov/symptomstesting/symptoms.html (CDC US 2020).

World Health Organization. Clinical Management of Severe Acute Respiratory Infection (SARI) When Covid-19 Disease is Suspected: Interim Guidance, 13 March 2020 (World Health Organization, 2020).

Epidemiology Working Group for NCIP Epidemic Response, Chinese Center for Disease Control and Prevention. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China. Zhonghua Liu Xing Bing. Xue Za Zhi 41 , 145–151 (2020).

Google Scholar  

Wang, M. et al. A precision medicine approach to managing 2019 novel coronavirus pneumonia. Precis. Clin. Med. 3 , 14–21 (2020).

Special Expert Group for Control of the Epidemic of Novel Coronavirus Pneumonia of the Chinese Preventive Medicine Association. An update on the epidemiological characteristics of novel coronavirus pneumonia (COVID-19). Zhonghua Liu Xing Bing. Xue Za Zhi 41 , 139–144 (2020).

Zhang, K. et al. Significant reduction of humoral response to SARS-CoV-2 4 months after the diagnosis of COVID-19. Precis. Clin. Med. https://doi.org/10.1093/pcmedi/pbaa036 (2020).

Zhang, K., Lau, J. Y.-N., Yang, L. & Ma, Z.-G. SARS-CoV-2 reinfection in two patients who have recovered from COVID-19. Precis. Clin. Med. 3 , 292–293 (2020).

Vrieze, J. D. More people are getting COVID-19 twice, suggesting immunity wanes quickly in some. Science https://doi.org/10.1126/science.abf7769 (2020).

Verity, R. et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect. Dis. https://doi.org/10.1016/S1473-3099(20)30243-7 (2020).

Chen, Z.-M. et al. Diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019 novel coronavirus. World J. Pediatr . https://doi.org/10.1007/s12519-020-00345-5 (2020).

Hong, H., Wang, Y., Chung, H.-T. & Chen, C.-J. Clinical characteristics of novel coronavirus disease 2019 (COVID-19) in newborns, infants and children. Pediatr. Neonatol . https://doi.org/10.1016/j.pedneo.2020.03.001 (2020).

Dong, Y. et al. Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatrics https://doi.org/10.1542/peds.2020-0702 (2020).

Ruan, Q., Yang, K., Wang, W., Jiang, L. & Song, J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intens. Care Med. https://doi.org/10.1007/s00134-020-05991-x (2020).

Wu, C. et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern. Med. https://doi.org/10.1001/jamainternmed.2020.0994 (2020).

Deng, Y. et al. Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study. Chin. Med. J. https://doi.org/10.1097/CM9.0000000000000824 (2020).

Yang, X. et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir. Med. https://doi.org/10.1016/S2213-2600(20)30079-5 (2020).

Liu, W. et al. Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease. Chin. Med. J. https://doi.org/10.1097/CM9.0000000000000775 (2020).

Lippi, G., Plebani, M. & Henry, B. M. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis. Clin. Chim. Acta 506 , 145–148 (2020).

CDC, U. Coronavirus Disease 2019 (COVID-19) Cases in the U.S. (2020).

Team, C. C.-R. Severe outcomes among patients with coronavirus disease 2019 (COVID-19) - United States, February 12-March 16, 2020. Morb. Mortal. Wkly Rep. 69 , 343–346 (2020).

Arentz, M. et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington State. JAMA https://doi.org/10.1001/jama.2020.4326 (2020).

McMichael, T. M. et al. Epidemiology of Covid-19 in a long-term care facility in King County, Washington. N. Engl. J. Med . https://doi.org/10.1056/NEJMoa2005412 (2020).

Mahase, E. Coronavirus covid-19 has killed more people than SARS and MERS combined, despite lower case fatality rate. BMJ 368 , m641 (2020).

Kissler, S. M., Tedijanto, C., Goldstein, E., Grad, Y. H. & Lipsitch, M. Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science 368 , 860–868 (2020).

Chen, S. et al. Fangcang shelter hospitals: a novel concept for responding to public health emergencies. Lancet 395 , 1305–1314 (2020).

Zhang, J. et al. Changes in contact patterns shape the dynamics of the COVID-19 outbreak in China. Science 368 , 1481–1486 (2020).

Greenhalgh, T., Schmid, M. B., Czypionka, T., Bassler, D. & Gruer, L. Face masks for the public during the covid-19 crisis. BMJ 369 , https://doi.org/10.1136/bmj.m1435 (2020).

Forster, P., Forster, L., Renfrew, C. & Forster, M. Phylogenetic network analysis of SARS-CoV-2 genomes. Proc. Natl Acad. Sci. USA 117 , 9241–9243 (2020).

Lu, R. et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 395 , 565–574 (2020).

Yan, R. et al. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 367 , 1444–1448 (2020).

Zou, X. et al. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front. Med . https://doi.org/10.1007/s11684-020-0754-0 (2020).

Cai, G., Bossé, Y., Xiao, F., Kheradmand, F. & Amos, C. I. Tobacco smoking increases the lung gene expression of ACE2, the receptor of SARS-CoV-2. Am. J. Respir. Crit. Care Med. 201 , 1557–1559 (2020).

Coutard, B. et al. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antivir. Res. 176 , 104742 (2020).

Hanff, T. C., Harhay, M. O., Brown, T. S., Cohen, J. B. & Mohareb, A. M. Is there an association between COVID-19 mortality and the renin-angiotensin system-a call for epidemiologic investigations. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa329 (2020).

Horby, P. et al. NERVTAG Paper on COVID-19 Variant of Concern B.1.1.7 (Crown Copyright, 2021).

Weisblum, Y. et al. Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. Elife 9 , https://doi.org/10.7554/eLife.61312 (2020).

Resende, P. C. et al. Spike E484K mutation in the first SARS-CoV-2 reinfection case confirmed in Brazil. Virological.org https://virological.org/t/spike-e484k-mutation-in-the-first-sars-cov-2-reinfection-case-confirmed-in-brazil-2020/584 (2021).

Liu, X. et al. General observation report on system anatomy of dead corpses of COVID-2019 pneumonia. J. Forensic Med. 36 , 21–23 (2020).

CAS   Google Scholar  

Wiersinga, W. J., Rhodes, A., Cheng, A. C., Peacock, S. J. & Prescott, H. C. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA 324 , 782–793 (2020).

Yu, F., Du, L., Ojcius, D. M., Pan, C. & Jiang, S. Measures for diagnosing and treating infections by a novel coronavirus responsible for a pneumonia outbreak originating in Wuhan, China. Microbes Infect. 22 , 74–79 (2020).

Yang, Y. et al. Evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and monitoring the viral shedding of 2019-nCoV infections. Preprint at medRxiv https://doi.org/10.1101/2020.02.11.20021493 (2020).

To, K. K.-W. et al. Consistent detection of 2019 novel coronavirus in saliva. Clin. Infect. Dis . https://doi.org/10.1093/cid/ciaa149 (2020).

Ni, L. et al. Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals. Immunity 52 , 971–977 (2020).

Xu, X. et al. Seroprevalence of immunoglobulin M and G antibodies against SARS-CoV-2 in China. Nat. Med. 26 , 1193–1195 (2020).

World Health Organization. Laboratory Testing for Coronavirus Disease (COVID-19) in Suspected Human Cases: Interim Guidance, 19 March 2020 (World Health Organization, Geneva, 2020).

Guo, L. et al. Profiling early humoral response to diagnose novel coronavirus disease (COVID-19). Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa310 (2020).

To, K. K.-W. et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect. Dis. https://doi.org/10.1016/S1473-3099(20)30196-1 (2020).

Sun, P. et al. Clinical characteristics of hospitalized patients with SARS-CoV-2 infection: a single arm meta-analysis. J. Med. Virol. 92 , 612–617 (2020).

Li, Z. et al. Development and clinical application of a rapid IgM-IgG combined antibody test for SARS-CoV-2 infection diagnosis. J. Med. Virol. https://doi.org/10.1002/jmv.25727 (2020).

Chen, C. et al. The epidemiological and radiographical characteristics of asymptomatic infections with the novel coronavirus (COVID-19): a systematic review and meta-analysis. Int. J. Infect. Dis. 104 , 458–464 (2021).

Zhang, K. et al. Clinically applicable AI system for accurate diagnosis, quantitative measurements, and prognosis of COVID-19 pneumonia using computed tomography. Cell 181 , 1423–1433 e1411 (2020).

Mei, X. et al. Artificial intelligence-enabled rapid diagnosis of patients with COVID-19. Nat. Med. 26 , 1224–1228 (2020).

Ting, D. S. W., Carin, L., Dzau, V. & Wong, T. Y. Digital technology and COVID-19. Nat. Med. 26 , 459–461 (2020).

Alimadadi, A. et al. Artificial intelligence and machine learning to fight COVID-19. Physiol. Genomics 52 , 200–202 (2020).

Kamel Boulos, M. N. & Geraghty, E. M. Geographical tracking and mapping of coronavirus disease COVID-19/severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic and associated events around the world: how 21st century GIS technologies are supporting the global fight against outbreaks and epidemics. Int. J. Health Geogr. 19 , 8 (2020).

Dong, E., Du, H. & Gardner, L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect. Dis. https://doi.org/10.1016/S1473-3099(20)30120-1 (2020).

Xu, X.-W. et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ 368 , m606 (2020).

Chen, Z. et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. Preprint at medRxiv https://doi.org/10.1101/2020.03.22.20040758 (2020).

Gautret, P. et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int. J. Antimicrob Agents https://doi.org/10.1016/j.ijantimicag.2020.105949 (2020).

Mitjà, O. et al. A cluster-randomized trial of hydroxychloroquine for prevention of Covid-19. N. Engl. J. Med. 384 , 417–427 (2021).

Horby, P. et al. Effect of hydroxychloroquine in hospitalized patients with Covid-19. N. Engl. J. Med. 383 , 2030–2040 (2020).

Rosenberg, E. S. et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA 323 , 2493–2502 (2020).

FDA. Hydroxycholoquine and Chloroquine Letter (FDA, 2020).

Falzarano, D. et al. Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin. Sci. Rep. 3 , 1686 (2013).

Article   PubMed   PubMed Central   CAS   Google Scholar  

Hung, I. F. et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet 395 , 1695–1704 (2020).

Young, B. E. et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA https://doi.org/10.1001/jama.2020.3204 (2020).

Kujawski, S. A. et al. Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States. Nat. Med. 26 , 861–868 (2020).

Article   CAS   Google Scholar  

Shen, C. et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA https://doi.org/10.1001/jama.2020.4783 (2020).

Roback, J. D. & Guarner, J. Convalescent plasma to treat COVID-19: possibilities and challenges. JAMA https://doi.org/10.1001/jama.2020.4940 (2020).

Liao, M. et al. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat. Med. 26 , 842–844 (2020).

Zhao, J. et al. Expert consensus on the use of corticosteroid in patients with 2019-nCoV pneumonia. Chin. J. Tuberculosis Respir. Dis. 43 , 183–184 (2020).

National Institutes of Health & Elvey, M. The COVID-19 Treatment Guidelines Panel’s Statement on the Use of Ivermectin for the Treatment of COVID-19 . Technical Report (National Institutes of Health, 2021).

Russell, C. D., Millar, J. E. & Baillie, J. K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 395 , 473–475 (2020).

Horby, P. et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report. N. Engl. J. Med. 384 , 693–704 (2020).

PubMed   Google Scholar  

Guan, W.-J. et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2002032 (2020).

Alhazzani, W. et al. Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Intens. Care Med. https://doi.org/10.1007/s00134-020-06022-5 (2020).

Ramanathan, K. et al. Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious diseases. Lancet Respir. Med. https://doi.org/10.1016/S2213-2600(20)30121-1 (2020).

Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382 , 727–733 (2020).

Gao, Q. et al. Rapid development of an inactivated vaccine candidate for SARS-CoV-2. Science https://doi.org/10.1126/science.abc1932 (2020).

Choi, Y. H. et al. Renal replacement therapy is independently associated with a lower risk of death in patients with severe acute kidney injury treated with targeted temperature management after out-of-hospital cardiac arrest. Crit. Care 24 , 115 (2020).

Zhu, F. C. et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 396 , 479–488 (2020).

Logunov, D. Y. et al. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet 396 , 887–897 (2020).

Folegatti, P. M. et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 396 , 467–478 (2020).

Xia, S. et al. Effect of an inactivated vaccine against SARS-CoV-2 on safety and immunogenicity outcomes: interim analysis of 2 randomized clinical trials. JAMA 324 , 951–960 (2020).

Jackson, L. A. et al. An mRNA vaccine against SARS-CoV-2 - preliminary report. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2022483 (2020).

Anderson, E. J. et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N. Engl. J. Med . https://doi.org/10.1056/NEJMoa2028436 (2020).

Mulligan, M. J. et al. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 586 , 589–593 (2020).

Walsh, E. E. et al. Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates. N. Engl. J. Med . https://doi.org/10.1056/NEJMoa2027906 (2020).

Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383 , 2603–2615 (2020).

Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384 , 403–416 (2021).

Kirby, J. Israel outpaced the world in vaccinations. Now it’s seeing the results. Vox (2021). https://www.vox.com/22262509/israel-covid-19-vaccinations-serious-illness-decline .

Castells, M. C. & Phillips, E. J. Maintaining safety with SARS-CoV-2 vaccines. N. Engl. J. Med. 384 , 643–649 (2020).

Jeyanathan, M. et al. Immunological considerations for COVID-19 vaccine strategies. Nat. Rev. Immunol. 20 , 615–632 (2020).

Ramasamy, M. N. et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. Lancet 396 , 1979–1993 (2021).

Voysey, M. et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 397 , 99–111 (2021).

Zhu, F. C. et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet 395 , 1845–1854 (2020).

Hu, Y. & Liu, C. CanSino says its COVID-19 vaccine has no serious adverse events, meets efficacy criteria in interim analysis. Global Times (2021). https://www.globaltimes.cn/page/202102/1214559.shtml .

Logunov, D. Y. et al. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet 397 , 671–681 (2021).

Xia, S. et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial. Lancet Infect. Dis. 21 , 39–51 (2021).

Zhang, Y. et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect. Dis. 21 , 181–192 (2021).

Keech, C. et al. Phase 1-2 trial of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine. N. Engl. J. Med. 383 , 2320–2332 (2020).

Yang, J. et al. A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity. Nature 586 , 572–577 (2020).

CDC US. Myths and Facts About COVID-19 Vaccines (CDC US, 2021).

Kemp, S. A. et al. SARS-CoV-2 evolution during treatment of chronic infection. Nature https://doi.org/10.1038/s41586-021-03291-y (2021).

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (91859203, 81871890), a Macao FDCT grant (0035/2020/A), the Science and Technology Project of Chengdu (2017-CY02-00030-GX), the Science and Technology Project of Sichuan (2020YFG0473), and Postdoctoral Program of West China Hospital, Sichuan University (2020HXBH084).

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These authors contributed equally: Chengdi Wang, Zhoufeng Wang, Guangyu Wang.

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Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, West China Medical School, Sichuan University, Chengdu, China

Chengdi Wang, Zhoufeng Wang & Weimin Li

School of Information and Communication Engineering, Beijing University of Posts and Telecommunications, Beijing, China

Guangyu Wang

Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hong Kong, China

Johnson Yiu-Nam Lau

Center for Biomedicine and Innovations, Faculty of Medicine, Macau University of Science and Technology, and University Hospital, Macau, China

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W.L. and K.Z. coordinate the manuscript preparation process; C.W., Z.W., G.W., and J.Y.-N.L. wrote the initial draft of the manuscript; W.L., K.Z., and J.Y.-N.L. edited and revised the manuscript. All authors reviewed and approved the final manuscript.

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Correspondence to Johnson Yiu-Nam Lau , Kang Zhang or Weimin Li .

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J.Y.-N.L. has an equity position in Avalon Biomedical Management, which has research projects related to SARS-CoV-2 diagnostics and COVID-19 vaccine development. K.Z. filed patents on COVID-19 diagnosis and vaccines. The other authors declare no competing interests.

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U.S. Tightens Rules on Risky Virus Research

A long-awaited new policy broadens the type of regulated viruses, bacteria, fungi and toxins, including those that could threaten crops and livestock.

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By Carl Zimmer and Benjamin Mueller

The White House has unveiled tighter rules for research on potentially dangerous microbes and toxins, in an effort to stave off laboratory accidents that could unleash a pandemic.

The new policy, published Monday evening, arrives after years of deliberations by an expert panel and a charged public debate over whether Covid arose from an animal market or a laboratory in China.

A number of researchers worried that the government had been too lax about lab safety in the past, with some even calling for the creation of an independent agency to make decisions about risky experiments that could allow viruses, bacteria or fungi to spread quickly between people or become more deadly. But others warned against creating restrictive rules that would stifle valuable research without making people safer.

The debate grew sharper during the pandemic, as politicians raised questions about the origin of Covid. Those who suggested it came from a lab raised concerns about studies that tweaked pathogens to make them more dangerous — sometimes known as “gain of function” research.

The new policy, which applies to research funded by the federal government, strengthens the government’s oversight by replacing a short list of dangerous pathogens with broad categories into which more pathogens might fall. The policy pays attention not only to human pathogens, but also those that could threaten crops and livestock. And it provides more details about the kinds of experiments that would draw the attention of government regulators.

The rules will take effect in a year, giving government agencies and departments time to update their guidance to meet the new requirements.

“It’s a big and important step forward,” said Dr. Tom Inglesby, the director of the Johns Hopkins Center for Health Security and a longtime proponent of stricter safety regulations. “I think this policy is what any reasonable member of the public would expect is in place in terms of oversight of the world’s most transmissible and lethal organisms.”

Still, the policy does not embrace the most aggressive proposals made by lab safety proponents, such as creating an independent regulatory agency. It also makes exemptions for certain types of research, including disease surveillance and vaccine development. And some parts of the policy are recommendations rather than government-enforced requirements.

“It’s a moderate shift in policy, with a number of more significant signals about how the White House expects the issue to be treated moving forward,” said Nicholas Evans, an ethicist at University of Massachusetts Lowell.

Experts have been waiting for the policy for more than a year. Still, some said they were surprised that it came out at such a politically fraught moment . “I wasn’t expecting anything, especially in an election year,” Dr. Evans said. “I’m pleasantly surprised.”

Under the new policy, scientists who want to carry out experiments will need to run their proposals past their universities or research institutions, which will to determine if the work poses a risk. Potentially dangerous proposals will then be reviewed by government agencies. The most scrutiny will go to experiments that could result in the most dangerous outcomes, such as those tweaking pathogens that could start a pandemic.

In a guidance document , the White House provided examples of research that would be expected to come under such scrutiny. In one case, they envisioned scientists trying to understand the evolutionary steps a pathogen needed to transmit more easily between humans. The researchers might try to produce a transmissible strain to study, for example, by repeatedly infecting human cells in petri dishes, allowing the pathogens to evolve more efficient ways to enter the cells.

Scientists who do not follow the new policy could become ineligible for federal funding for their work. Their entire institution may have its support for life science research cut off as well.

One of the weaknesses of existing policies is that they only apply to funding given out by the federal government. But for years , the National Institutes of Health and other government agencies have struggled with stagnant funding, leading some researchers to turn instead to private sources. In recent years, for example, crypto titans have poured money into pandemic prevention research.

The new policy does not give the government direct regulation of privately funded research. But it does say that research institutions that receive any federal money for life-science research should apply a similar oversight to scientists doing research with support from outside the government.

“This effectively limits them, as the N.I.H. does a lot of work everywhere in the world,” Dr. Evans said.

The new policy takes into account the advances in biotechnology that could lead to new risks. When pathogens become extinct, for example, they can be resurrected by recreating their genomes. Research on extinct pathogens will draw the highest levels of scrutiny.

Dr. Evans also noted that the new rules emphasize the risk that lab research can have on plants and animals. In the 20th century, the United States and Russia both carried out extensive research on crop-destroying pathogens such as wheat-killing fungi as part of their biological weapons programs. “It’s significant as a signal the White House is sending,” Dr. Evans said.

Marc Lipsitch, an epidemiologist at Harvard and a longtime critic of the government’s policy, gave the new one a grade of A minus. “I think it’s a lot clearer and more specific in many ways than the old guidance,” he said. But he was disappointed that the government will not provide detailed information to the public about the risky research it evaluates. “The transparency is far from transparent,” he said.

Scientists who have warned of the dangers of impeding useful virus research were also largely optimistic about the new rules.

Gigi Gronvall, a biosafety specialist at the Johns Hopkins Bloomberg School of Public Health, said the policy’s success would depend on how federal health officials interpreted it, but applauded the way it recognized the value of research needed during a crisis, such as the current bird flu outbreak .

“I was cautiously optimistic in reading through it,” she said of the policy. “It seems like the orientation is for it to be thoughtfully implemented so it doesn’t have a chilling effect on needed research.”

Anice Lowen, an influenza virologist at Emory University, said the expanded scope of the new policy was “reasonable.” She said, for instance, that the decision not to create an entirely new review body helped to alleviate concerns about how unwieldy the process might become.

Still, she said, ambiguities in the instructions for assessing risks in certain experiments made it difficult to know how different university and health officials would police them.

“I think there will be more reviews carried out, and more research will be slowed down because of it,” she said.

Carl Zimmer covers news about science for The Times and writes the Origins column . More about Carl Zimmer

Benjamin Mueller reports on health and medicine. He was previously a U.K. correspondent in London and a police reporter in New York. More about Benjamin Mueller

Sarah Harding breast cancer research project is successfully identifying at-risk young women

Sarah Harding died aged 39 after being diagnosed with breast cancer. One of the Girls Aloud singer's final hopes was to find ways of spotting the disease early when it's easier to treat.

By Charlotte Leeming, north of England correspondent

Sunday 19 May 2024 02:43, UK

A groundbreaking breast cancer research project launched in memory of the late Girls Aloud singer Sarah Harding is already successfully identifying young women at increased risk of getting the disease.

The BCAN-RAY (Breast Cancer Risk Assessment in Young Women) was launched a year ago in the singer's name after she died from the disease in 2021 at the age of 39.

While she was having treatment, the star said she was "really keen" for more research into why young women are being diagnosed without a family history of the disease.

One of the singer's final hopes was to find ways of spotting the disease early when it's easier to treat.

The BCAN-RAY is one of the only projects in the world trying to identify which women in their 30s are most at risk.

About 2,300 women under 40 are diagnosed with the disease each year in the UK, according to Breast Cancer Now.

The two-year study is using money from Cancer Research UK, the Christie Charity, and the Sarah Harding Breast Cancer Appeal - backed by her family and former bandmates.

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It looks at risk factors most commonly found in young women with the disease and will form a model to identify them in future.

Read more: Proteins in blood could warn of cancer seven years before diagnosis New cancer treatment gives hope as diagnoses rise Girls Aloud kick off reunion tour dedicated to Sarah Harding

Anna Housley, 39, from Hale, Greater Manchester, is one of the women taking part in the trial. After being tested last year the mother of two was surprised to find she's at increased risk.

With no history of the disease in her family, she told Sky News: "I'm really grateful that I have been found because now I know that I'm going to be looked after and I can be screened."

Keep up with all the latest news from the UK and around the world by following Sky News

Speaking about the work of Harding, she said: "All I can say really is thanks to her for being such a brave advocate to young women."

The new information means she's now eligible for annual mammograms and medication should she want it.

It's hoped all women will eventually be able to have a risk assessment when they reach 30.

A thousand women in the Greater Manchester area will take part, including 250 with breast cancer who don't have a family history of the disease.

Saliva samples will hopefully help experts identify certain types and patterns of genes that could raise a woman's risk.

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These will be considered with factors such as period timing, breast tissue density, alcohol consumption and use of the pill.

Harding's consultant Dr Sacha Howell from Manchester University NHS Foundation Trust, who is leading the study, said of the singer: "I think she'd be absolutely thrilled that she was part of this and her legacy is that we will be helping more and more young women like her.

"But what we're all hoping is that by detecting those cancers earlier, they won't unfortunately have that end result that Sarah did, which was to pass away with the disease."

Harding's legacy won't just be her successful music career, it will also be her work in raising awareness around breast cancer and potentially giving many more women in their 30s a future.

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Taking RNAi from interesting science to impactful new treatments

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There are many hurdles to clear before a research discovery becomes a life-changing treatment for patients. That’s especially true when the treatments being developed represent an entirely new class of medicines. But overcoming those obstacles can revolutionize our ability to treat diseases.

Few companies exemplify that process better than Alnylam Pharmaceuticals. Alnylam was founded by a group of MIT-affiliated researchers who believed in the promise of a technology — RNA interference, or RNAi.

The researchers had done foundational work to understand how RNAi, which is a naturally occurring process, works to silence genes through the degradation of messenger RNA. But it was their decision to found Alnylam in 2002 that attracted the funding and expertise necessary to turn their discoveries into a new class of medicines. Since that decision, Alnylam has made remarkable progress taking RNAi from an interesting scientific discovery to an impactful new treatment pathway.

Today Alnylam has five medicines approved by the U.S. Food and Drug Administration (one Alnylam-discovered RNAi therapeutic is licensed to Novartis) and a rapidly expanding clinical pipeline. The company’s approved medicines are for debilitating, sometimes fatal conditions that many patients have grappled with for decades with few other options.

The company estimates its treatments helped more than 5,000 patients in 2023 alone. Behind that number are patient stories that illustrate how Alnylam has changed lives. A mother of three says Alnylam’s treatments helped her take back control of her life after being bed-ridden with attacks associated with the rare genetic disease acute intermittent porphyria (AIP). Another patient reported that one of the company’s treatments helped her attend her daughter’s wedding. A third patient, who had left college due to frequent AIP attacks, was able to return to school.

These days Alnylam is not the only company developing RNAi-based medicines. But it is still a pioneer in the field, and the company’s founders — MIT Institute Professor Phil Sharp, Professor David Bartel, Professor Emeritus Paul Schimmel, and former MIT postdocs Thomas Tuschl and Phillip Zamore — see Alnylam as a champion for the field more broadly.

“Alnylam has published more than 250 scientific papers over 20 years,” says Sharp, who currently serves as chair of Alnylam’s scientific advisory board. “Not only did we do the science, not only did we translate it to benefit patients, but we also described every step. We established this as a modality to treat patients, and I’m very proud of that record.”

Pioneering RNAi development

MIT’s involvement in RNAi dates back to its discovery. Before Andrew Fire PhD ’83 shared a Nobel Prize for the discovery of RNAi in 1998, he worked on understanding how DNA was transcribed into RNA, as a graduate student in Sharp’s lab.

After leaving MIT, Fire and collaborators showed that double-stranded RNA could be used to silence specific genes in worms. But the biochemical mechanisms that allowed double-stranded RNA to work were unknown until MIT professors Sharp, Bartel, and Ruth Lehmann, along with Zamore and Tuschl, published foundational papers explaining the process. The researchers developed a system for studying RNAi and showed how RNAi can be controlled using different genetic sequences. Soon after Tuschl left MIT, he showed that a similar process could also be used to silence specific genes in human cells, opening up a new frontier in studying genes and ultimately treating diseases.

“Tom showed you could synthesize these small RNAs, transfect them into cells, and get a very specific knockdown of the gene that corresponded to that the small RNAs,” Bartel explains. “That discovery transformed biological research. The ability to specifically knockdown a mammalian gene was huge. You could suddenly study the function of any gene you were interested in by knocking it down and seeing what happens. … The research community immediately started using that approach to study the function of their favorite genes in mammalian cells.”

Beyond illuminating gene function, another application came to mind.

“Because almost all diseases are related to genes, could we take these small RNAs and silence genes to treat patients?” Sharp remembers wondering.

To answer the question, the researchers founded Alnylam in 2002. (They recruited Schimmel, a biotech veteran, around the same time.) But there was a lot of work to be done before the technology could be tried in patients. The main challenge was getting RNAi into the cytoplasm of the patients’ cells.

“Through work in Dave Bartel and Phil Sharp's lab, among others, it became evident that to make RNAi into therapies, there were three problems to solve: delivery, delivery, and delivery,” says Alnylam Chief Scientific Officer Kevin Fitzgerald, who has been with the company since 2005.

Early on, Alnylam collaborated with MIT drug delivery expert and Institute Professor Bob Langer. Eventually, Alnylam developed the first lipid nanoparticles (LNPs) that could be used to encase RNA and deliver it into patient cells. LNPs were later used in the mRNA vaccines for Covid-19.

“Alnylam has invested over 20 years and more than $4 billion in RNAi to develop these new therapeutics,” Sharp says. “That is the means by which innovations can be translated to the benefit of society.”

From scientific breakthrough to patient bedside

Alnylam received its first FDA approval in 2018 for treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis, a rare and fatal disease. It doubled as the first RNAi therapeutic to reach the market and the first drug approved to treat that condition in the United States.

“What I keep in mind is, at the end of the day for certain patients, two months is everything,” Fitzgerald says. “The diseases that we’re trying to treat progress month by month, day by day, and patients can get to a point where nothing is helping them. If you can move their disease by a stage, that’s huge.”

Since that first treatment, Alnylam has updated its RNAi delivery system — including by conjugating small interfering RNAs to molecules that help them gain entry to cells — and earned approvals to treat other rare genetic diseases along with high cholesterol (the treatment licensed to Novartis). All of those treatments primarily work by silencing genes that encode for the production of proteins in the liver, which has proven to be the easiest place to deliver RNAi molecules. But Alnylam’s team is confident they can deliver RNAi to other areas of the body, which would unlock a new world of treatment possibilities. The company has reported promising early results in the central nervous system and says a phase one study last year was the first RNAi therapeutic to demonstrate gene silencing in the human brain.

“There’s a lot of work being done at Alnylam and other companies to deliver these RNAis to other tissues: muscles, immune cells, lung cells, etc.,” Sharp says. “But to me the most interesting application is delivery to the brain. We think we have a therapeutic modality that can very specifically control the activity of certain genes in the nervous system. I think that’s extraordinarily important, for diseases from Alzheimer’s to schizophrenia and depression.”

The central nervous system work is particularly significant for Fitzgerald, who watched his father struggle with Parkinson’s.

“Our goal is to be in every organ in the human body, and then combinations of organs, and then combinations of targets within individual organs, and then combinations of targets within multi-organs,” Fitzgerald says. “We’re really at the very beginning of what this technology is going do for human health.”

It’s an exciting time for the RNAi scientific community, including many who continue to study it at MIT. Still, Alnylam will need to continue executing in its drug development efforts to deliver on that promise and help an expanding pool of patients.

“I think this is a real frontier,” Sharp says. “There’s major therapeutic need, and I think this technology could have a huge impact. But we have to prove it. That’s why Alnylam exists: to pursue new science that unlocks new possibilities and discover if they can be made to work. That, of course, also why MIT is here: to improve lives.”

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Are Markups Driving the Ups and Downs of Inflation?

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FRBSF Economic Letter 2024-12 | May 13, 2024

How much impact have price markups for goods and services had on the recent surge and the subsequent decline of inflation? Since 2021, markups have risen substantially in a few industries such as motor vehicles and petroleum. However, aggregate markups—which are more relevant for overall inflation—have generally remained flat, in line with previous economic recoveries over the past three decades. These patterns suggest that markup fluctuations have not been a main driver of the ups and downs of inflation during the post-pandemic recovery.

In the recovery from the pandemic, U.S. inflation surged to a peak of over 7% in June 2022 and has since declined to 2.7% in March 2024, as measured by the 12-month change in the personal consumption expenditures (PCE) price index. What factors have been driving the ups and downs of inflation? Production costs are traditionally considered a main contributor, particularly costs stemming from fluctuations in demand for and supply of goods and services. As demand for their products rises, companies need to hire more workers and buy more intermediate goods, pushing up production costs. Supply chain disruptions can also push up the cost of production. Firms may pass on all or part of the cost increases to consumers by raising prices. Thus, an important theoretical linkage runs from cost increases to inflation. Likewise, decreases in costs should lead to disinflation.

Labor costs are an important factor of production costs and are often useful for gauging inflationary pressures. However, during the post-pandemic surge in inflation, nominal wages rose more slowly than prices, such that real labor costs were falling until early 2023. By contrast, disruptions to global supply chains pushed up intermediate goods costs, contributing to the surge in inflation (see, for example, Liu and Nguyen 2023). However, supply chains have more direct impacts on goods inflation than on services inflation, which also rose substantially.

In this Economic Letter , we consider another factor that might drive inflation fluctuations: changes in firms’ pricing power and markups. An increase in pricing power would be reflected in price-cost markups, leading to higher inflation; likewise, a decline in pricing power and markups could alleviate inflation pressures. We use industry-level measures of markups to trace their evolving impact on inflation during the current expansion. We find that markups rose substantially in some sectors, such as the motor vehicles industry. However, the aggregate markup across all sectors of the economy, which is more relevant for inflation, has stayed essentially flat during the post-pandemic recovery. This is broadly in line with patterns during previous business cycle recoveries. Overall, our analysis suggests that fluctuations in markups were not a main driver of the post-pandemic surge in inflation, nor of the recent disinflation that started in mid-2022.

Potential drivers of inflation: Production costs and markups

To support households and businesses during the pandemic, the Federal Reserve lowered the federal funds rate target to essentially zero, and the federal government provided large fiscal transfers and increased unemployment benefits. These policies boosted demand for goods and services, especially as the economy recovered from the depth of the pandemic.

The increase in overall demand, combined with supply shortages, boosted the costs of production, contributing to the surge in inflation during the post-pandemic recovery. Although labor costs account for a large part of firms’ total production costs, real labor costs were falling between early 2021 and mid-2022 such that the increases in prices outpaced those in nominal wages. This makes it unlikely that labor costs were driving the surge in inflation.

Instead, we focus on another potential alternative driver of inflation that resulted from firms’ ability to adjust prices, known as pricing power. As demand for goods surged early in the post-pandemic recovery, companies may have had a greater ability to raise their prices above their production costs, a gap known as markups. Following a sharp drop in spending at the height of the pandemic, people may have become eager to resume normal spending patterns and hence more tolerant to price increases than in the past. In fact, growth of nonfinancial corporate profits accelerated in the early part of the recovery (see Figure 1), suggesting that companies had increased pricing power. Some studies have pointed to the strong growth in nonfinancial corporate profits in 2021 as evidence that increased markups have contributed to inflation (see, for example, Weber and Wasmer 2023). However, the figure also shows that growth in corporate profits is typically volatile. Corporate profits tend to rise in the early stages of economic recoveries. Data for the current recovery show that the increase in corporate profits is not particularly pronounced compared with previous recoveries.

Figure 1 Profit growth for nonfinancial businesses

More importantly, corporate profits are an imperfect measure of a firm’s pricing power because several other factors can drive changes in profitability. For instance, much of the recent rise in corporate profits can be attributed to lower business taxes and higher subsidies from pandemic-related government support, as well as lower net interest payments due to monetary policy accommodation (Pallazzo 2023).

Instead of relying on profits as a measure of pricing power, we construct direct measures of markups based on standard economic models. Theory suggests that companies set prices as a markup over variable production costs, and that markup can be inferred from the share of a firm’s revenue spent on a given variable production factor, such as labor or intermediate goods. Over the period of data we use, we assume that the specific proportion of a company’s production costs going toward inputs does not change. If the share of a firm’s revenue used for inputs falls, it would imply a rise in the firm’s price-cost margin or markup. In our main analysis, we use industry-level data from the Bureau of Economic Analysis (BEA) to compute markups based on the share of revenue spent on intermediate inputs. Our results are similar if we instead use the share of revenue going toward labor costs.

We compare the evolution of markups to that of prices, as measured by the PCE price index, since the recovery from the pandemic. In constructing this price index, the BEA takes into account changes in product characteristics (for instance, size) that could otherwise bias the inflation measure by comparing the prices of inherently different products over time. Similarly, based upon standard economic theory, our markup measure implicitly captures changes in those characteristics (see, for example, Aghion et al. 2023).

The post-pandemic evolution of markups

We examine the evolution of markups in each industry since the third quarter of 2020, the start of the post-pandemic recovery. Figure 2 shows that some sectors, such as the motor vehicles and petroleum industries, experienced large cumulative increases in markups during the recovery. Markups also rose substantially in general merchandise, such as department stores, and for other services, such as repair and maintenance, personal care, and laundry services. Since the start of the expansion, markups in those industries rose by over 10%—comparable in size to the cumulative increases over the same period in the core PCE price index, which excludes volatile food and energy components. However, the surge in inflation through June 2022 was broad based, with prices also rising substantially outside of these sectors. Thus, understanding the importance of markups for driving inflation requires a macroeconomic perspective that examines the evolution of aggregate markups across all sectors of the economy.

Figure 2 Cumulative changes in markups for salient industries

The role of aggregate markups in the economy

To assess how much markup changes contribute to movements in inflation more broadly, we use our industry-level measurements to calculate an aggregate markup at the macroeconomic level. We aggregate the cumulative changes in industry markups, applying two different weighting methods, as displayed in Figure 3. In the first method (green line), we match our industry categories to the spending categories in the core PCE price index for ease of comparison; we then use the PCE weights for each category to compute the aggregate markup. Alternatively, we use each industry’s cost weights to compute the aggregate markup (blue line). Regardless of the weighting method, Figure 3 shows that aggregate markups have stayed essentially flat since the start of the recovery, while the core PCE price index (gray line) rose by more than 10%. Thus, changes in markups are not likely to be the main driver of inflation during the recovery, which aligns with results from Glover, Mustre-del-Río, and von Ende-Becker (2023) and Hornstein (2023) using different methodologies or data. Markups also have not played much of a role in the slowing of inflation since the summer of 2022.

Figure 3 Cumulative changes in aggregate markups and prices

Moreover, the path of aggregate markups over the past three years is not unusual compared with previous recoveries. Figure 4 shows the cumulative changes in aggregate markups since the start of the current recovery (dark blue line), alongside aggregate markups following the 1991 (green line), 2001 (yellow line), and 2008 (light blue line) recessions. Aggregate markups have stayed roughly constant throughout all four recoveries.

Figure 4 Cumulative changes of aggregate markups in recoveries

Firms’ pricing power may change over time, resulting in markup fluctuations. In this Letter , we examine whether increases in markups played an important role during the inflation surge between early 2021 and mid-2022 and if declines in markups have contributed to disinflation since then. Using industry-level data, we show that markups did rise substantially in a few important sectors, such as motor vehicles and petroleum products. However, aggregate markups—the more relevant measure for overall inflation—have stayed essentially flat since the start of the recovery. As such, rising markups have not been a main driver of the recent surge and subsequent decline in inflation during the current recovery.

Aghion, Philippe, Antonin Bergeaud, Timo Boppart, Peter J. Klenow, and Huiyu Li. 2023. “A Theory of Falling Growth and Rising Rents.”  Review of Economic Studies  90(6), pp.2,675-2,702.

Glover, Andrew, José Mustre-del-Río, and Alice von Ende-Becker. 2023. “ How Much Have Record Corporate Profits Contributed to Recent Inflation? ” FRB Kansas City Economic Review 108(1).

Hornstein, Andreas. 2023. “ Profits and Inflation in the Time of Covid .” FRB Richmond Economic Brief 23-38 (November).

Liu, Zheng, and Thuy Lan Nguyen. 2023. “ Global Supply Chain Pressures and U.S. Inflation .” FRBSF Economic Letter 2023-14 (June 20).

Palazzo, Berardino. 2023. “ Corporate Profits in the Aftermath of COVID-19 .” FEDS Notes , Federal Reserve Board of Governors, September 8.

Weber, Isabella M. and Evan Wasner. 2023. “Sellers’ Inflation, Profits and Conflict: Why Can Large Firms Hike Prices in an Emergency?” Review of Keynesian Economics 11(2), pp. 183-213.

Opinions expressed in FRBSF Economic Letter do not necessarily reflect the views of the management of the Federal Reserve Bank of San Francisco or of the Board of Governors of the Federal Reserve System. This publication is edited by Anita Todd and Karen Barnes. Permission to reprint portions of articles or whole articles must be obtained in writing. Please send editorial comments and requests for reprint permission to [email protected]

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New research initiative tackles pressing global development issues

By alison fromme cornell sc johnson college of business.

Fundamental challenges in food insecurity, poverty, agriculture, health, education and markets form the focus of Collaboration for International Development Economics Research (CIDER) , a new initiative launched by the Office of the Provost, the SC Johnson College of Business, the College of Agriculture and Life Sciences, the College of Arts and Sciences and the Cornell Jeb E. Brooks School of Policy.

“CIDER builds on a long history of Cornell research and engagement in the economies of nations, particularly developing and emerging economies challenged by global economic forces,” said Provost Michael I. Kotlikoff. “This initiative expands the interdisciplinary focus of these efforts, bringing economists, social scientists, policy experts and agricultural experts together to pursue solutions to some of our most difficult global challenges.”

Hosted by the SC Johnson College, CIDER unites 24 faculty across campus and the world, along with students, staff, researchers and external partners, to create and share knowledge. CIDER’s activities will encompass research, workshops, seminars, internships, career mentoring and continuing-education coursework.

“We’re delighted to embark on this new collaborative effort in development economics,” said Andrew Karolyi, the Charles Field Knight Dean of the Cornell SC Johnson College of Business. “CIDER taps into existing expertise and a grand legacy of intellectual leadership at Cornell going back decades. I can’t wait to see the tangible impact CIDER makes on campus and around the world.”

CIDER’s inaugural faculty director is Chris Barrett , the Stephen B. and Janice G. Ashley Professor of Applied Economics and Management in the Charles H. Dyson School of Applied Economics and Management and professor in the Brooks School.

“We expect CIDER will further reinforce Cornell's already formidable reputation in this space,” Barrett said. The university’s impact in development economics was established over many decades and reinforced when standard measures of poverty and food insecurity were developed here in the 1980s. Now, CIDER provides a forum to collaborate on large-scale projects, advance policy-relevant research and train early career scholars and practitioners.

Through a workshop hosted by CIDER on May 10, the center is already encouraging new collaborations in East African dryland drought research, risk management and policy.

The World Bank, the African Development Bank, private organizations and multiple East African national governments are currently investing nearly $1 billion in the region to address drought, Barrett said.

“The efficacy and the impact of these massive investments can be directly influenced by research findings,” he said. “Indeed, research by Cornell and partners going back to the late 2000s underpins the initiative. We’re now working to produce timely policy-relevant, clearly communicated and rigorous research that can inform that effort.”

Among other presentations at the workshop, Karlijn Morsink , Utrecht University economist and CIDER-affiliated adjunct associate professor at the Dyson School, discussed her work leading the evaluation of World Bank programs in the region and share opportunities for Cornell faculty and student involvement.

“This workshop and the collaborations it represents offer just one example,” Barrett said. “We look to scale this type of effort across a range of different domains.”

CIDER will also support early career mentoring through two formal programs. Structural Transformation of Agriculture and Rural Spaces (STARS) , an existing Cornell program, previously paired early career researchers who earned degrees in Africa with mentors at Cornell and affiliated institutions. Now under CIDER’s umbrella, STARS is open to scholars across all low- and lower-middle-income countries.

Additionally, a predoctoral program for scholars who have not yet earned advanced degrees will provide one to three years of research experience and professional development training with core faculty. One predoctoral fellow already began work in January, and three more arrive this summer.

Building professional networks, increasing research capacity, disseminating best practices in the field and shaping early career researchers for the next generation are at the heart of CIDER’s mission, Barrett said. “This is a really exciting venture.”

Alison Fromme is a writer for the Cornell SC Johnson College of Business.

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From ‘Yellow Peril’ to COVID-19: New book takes unflinching look at anti-Asian racism

People holding "Stop Asian hate" signs during a rally in San Francisco in 2021. (Credit: Jason Leung/Unsplash )  

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More than 150 years ago, some 15,000 Chinese workers arrived in the U.S. to help construct the country’s first transcontinental railroad, which connected the West Coast with the East Coast’s rail network.

These Chinese laborers received lower wages than their white counterparts for the same job and endured worse living conditions. 

Over the past century and a half, discrimination against Asians has persisted. 

During World War II, the U.S. incarcerated hundreds of thousands of Japanese Americans; after the terrorist attacks of Sept. 11, 2001, hate incidents against Middle Eastern and South Asian communities soared; following the coronavirus outbreak, hatred directed at people of Asian heritage spread across the globe . 

After witnessing a surge in anti-Asian hate incidents during the height of the COVID-19 pandemic, Ethnic Studies Professor Jennifer Ho collected a diverse range of stories from authors of Asian heritage worldwide and released the edited volume “ Global Anti-Asian Racism ” in February.

“If you know someone who's Asian, living anywhere in this world, they have been subjected to and have thought about being the target of violence and racism,” says Ho, a Chinese American woman who was herself subject to anti-Asian harassment at the start of the COVID-19 pandemic.

May marks the 155th anniversary of the railroad’s completion and the annual celebration of Asian American and Pacific Islander (AAPI) Heritage Month. CU Boulder Today spoke with Ho, director of the  Center for Humanities & the Arts , about her new book and the importance of supporting AAPI communities year-round. 

Jennifer Ho

What ignited the recent wave of anti-Asian racism?

The COVID-19 virus originated out of China. That’s really all it took, given the centuries-long circulation of “yellow peril” rhetoric, which describes the Western fears that East Asians would take over the West and disrupt Western values. 

The peak of the recent wave of anti-Asian racism was in March of 2021 when a gunman in Atlanta, Georgia, killed eight people, six of whom were Asian women. Around the same time, we saw multiple videos of Asian elders being punched in the face in various Chinatowns across the U.S.  

Racism against Asian Americans is not new. How are the recent events different?

The recent events are specifically targeting Chinese or people who have East Asian features and are misidentified as Chinese. But this violence is rooted in a longstanding history of targeting Asians in the U.S. simply because they look different. 

In the U.S. context, white supremacy is the main driving force of anti-Asian racism. White supremacy perpetuates the belief that Asians never inherently belong in U.S. spaces and that Asians are always hyphenated Americans. For example, I'm never going to be treated or seen as someone who is just plain American, because in the minds of most people in the U.S., an American is someone with a white face. 

Has the spike in anti-Asian hate incidents simmered down?

Thankfully, we have not had another kind of mass fatality after Atlanta and Indianapolis. But that's not to say that anti-Asian racism isn't happening. For example, Florida recently passed a law banning Chinese nationals from purchasing real estate . The kind of anti-Chinese rhetoric that is constantly in the news means that if there's ever some kind of security threat, whether through a virus or an Asian entity, we will likely see another uptick in anti-Asian racism.

How are Asian American communities responding?

Over the years, there has been a growing collective sense of what it means to be Asian American. About 15 years ago, a survey revealed only 20% of Asian Americans identified themselves as Asian American. Instead, the vast majority of people of Asian heritage in the U.S. identified first and foremost with their ethnic background, like Chinese, Chinese American, Indian, Indian American, South Asian and so on.

In response to the recent waves of anti-Asian racism, more people realized if you have East Asian features, you can be misidentified as Chinese and become the target of hate incidents. As a result, the attacks that happened against one Asian ethnic group become attacks against all Asian ethnic groups. This led to a greater understanding and awareness that Asian Americans, as a racial collective body, need to come together in solidarity to protect one another.

What inspired you to create this book?

I had done a few public-facing pieces during COVID-19 on anti-Asian racism . After one of them was published, I was contacted by people from around the world asking me if there were resources that I knew of in their countries similar to the Stop AAPI Hate coalition in the U.S. 

My expertise is very limited to a U.S. context, and I didn't have other resources to share. So when I was contacted to develop a volume on global anti-Asian racism, I was grateful to curate a collection of essays from a diverse array of scholars from around the world. 

What do you hope the readers will take away from this book? 

I do hope the book can reach out to a more general readership, outside of a classroom space, outside of the ivory tower of academia. I hope that people who have a curiosity about anti-Asian racism, whether they're Asian-identified or not, will read about various forms of anti-Asian racism that have happened around the globe. 

During COVID-19, I saw colleagues step up and be interviewed by a number of news outlets, write opinion pieces and share their expertise on what they knew about anti-Asian racism with the world. I hope, very humbly, that this book can be my contribution. 

Can society break the stereotypes around Asian Americans and Pacific Islanders? 

Breaking stereotypes is always just hard. In the U.S., we really like binary systems, like our political parties. We prefer things to be categorized as either good or bad. But the reality is always more complicated than that. 

But I do have hope. The way we are now starting to understand that gender is not binary but on a spectrum and fluid makes me hopeful that one day we can do that with race. 

What kind of stories would you like to see told?

The stories of Asians in America is yet to be told publicly, broadly and widely. I wish more people would do stories about the communities, not just when there's something bad happening to Asian Americans in America, but out of genuine curiosity about who Asian Americans are.

We are this really wonderful, complex group. It's not like we're all good, or we're all bad. It's not like we all excel in school. But we have really interesting stories to tell. I wish more people wanted to tell the stories, and more of the public would be curious about these stories outside of AAPI month.   

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CU Boulder Today regularly publishes Q&As with our faculty members weighing in on news topics through the lens of their scholarly expertise and research/creative work. The responses here reflect the knowledge and interpretations of the expert and should not be considered the university position on the issue. All publication content is subject to edits for clarity, brevity and  university style guidelines .

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McKinsey Global Private Markets Review 2024: Private markets in a slower era

At a glance, macroeconomic challenges continued.

McKinsey Global Private Markets Review 2024: Private markets: A slower era

If 2022 was a tale of two halves, with robust fundraising and deal activity in the first six months followed by a slowdown in the second half, then 2023 might be considered a tale of one whole. Macroeconomic headwinds persisted throughout the year, with rising financing costs, and an uncertain growth outlook taking a toll on private markets. Full-year fundraising continued to decline from 2021’s lofty peak, weighed down by the “denominator effect” that persisted in part due to a less active deal market. Managers largely held onto assets to avoid selling in a lower-multiple environment, fueling an activity-dampening cycle in which distribution-starved limited partners (LPs) reined in new commitments.

About the authors

This article is a summary of a larger report, available as a PDF, that is a collaborative effort by Fredrik Dahlqvist , Alastair Green , Paul Maia, Alexandra Nee , David Quigley , Aditya Sanghvi , Connor Mangan, John Spivey, Rahel Schneider, and Brian Vickery , representing views from McKinsey’s Private Equity & Principal Investors Practice.

Performance in most private asset classes remained below historical averages for a second consecutive year. Decade-long tailwinds from low and falling interest rates and consistently expanding multiples seem to be things of the past. As private market managers look to boost performance in this new era of investing, a deeper focus on revenue growth and margin expansion will be needed now more than ever.

Perspectives on a slower era in private markets

Global fundraising contracted.

Fundraising fell 22 percent across private market asset classes globally to just over $1 trillion, as of year-end reported data—the lowest total since 2017. Fundraising in North America, a rare bright spot in 2022, declined in line with global totals, while in Europe, fundraising proved most resilient, falling just 3 percent. In Asia, fundraising fell precipitously and now sits 72 percent below the region’s 2018 peak.

Despite difficult fundraising conditions, headwinds did not affect all strategies or managers equally. Private equity (PE) buyout strategies posted their best fundraising year ever, and larger managers and vehicles also fared well, continuing the prior year’s trend toward greater fundraising concentration.

The numerator effect persisted

Despite a marked recovery in the denominator—the 1,000 largest US retirement funds grew 7 percent in the year ending September 2023, after falling 14 percent the prior year, for example 1 “U.S. retirement plans recover half of 2022 losses amid no-show recession,” Pensions and Investments , February 12, 2024. —many LPs remain overexposed to private markets relative to their target allocations. LPs started 2023 overweight: according to analysis from CEM Benchmarking, average allocations across PE, infrastructure, and real estate were at or above target allocations as of the beginning of the year. And the numerator grew throughout the year, as a lack of exits and rebounding valuations drove net asset values (NAVs) higher. While not all LPs strictly follow asset allocation targets, our analysis in partnership with global private markets firm StepStone Group suggests that an overallocation of just one percentage point can reduce planned commitments by as much as 10 to 12 percent per year for five years or more.

Despite these headwinds, recent surveys indicate that LPs remain broadly committed to private markets. In fact, the majority plan to maintain or increase allocations over the medium to long term.

Investors fled to known names and larger funds

Fundraising concentration reached its highest level in over a decade, as investors continued to shift new commitments in favor of the largest fund managers. The 25 most successful fundraisers collected 41 percent of aggregate commitments to closed-end funds (with the top five managers accounting for nearly half that total). Closed-end fundraising totals may understate the extent of concentration in the industry overall, as the largest managers also tend to be more successful in raising non-institutional capital.

While the largest funds grew even larger—the largest vehicles on record were raised in buyout, real estate, infrastructure, and private debt in 2023—smaller and newer funds struggled. Fewer than 1,700 funds of less than $1 billion were closed during the year, half as many as closed in 2022 and the fewest of any year since 2012. New manager formation also fell to the lowest level since 2012, with just 651 new firms launched in 2023.

Whether recent fundraising concentration and a spate of M&A activity signals the beginning of oft-rumored consolidation in the private markets remains uncertain, as a similar pattern developed in each of the last two fundraising downturns before giving way to renewed entrepreneurialism among general partners (GPs) and commitment diversification among LPs. Compared with how things played out in the last two downturns, perhaps this movie really is different, or perhaps we’re watching a trilogy reusing a familiar plotline.

Dry powder inventory spiked (again)

Private markets assets under management totaled $13.1 trillion as of June 30, 2023, and have grown nearly 20 percent per annum since 2018. Dry powder reserves—the amount of capital committed but not yet deployed—increased to $3.7 trillion, marking the ninth consecutive year of growth. Dry powder inventory—the amount of capital available to GPs expressed as a multiple of annual deployment—increased for the second consecutive year in PE, as new commitments continued to outpace deal activity. Inventory sat at 1.6 years in 2023, up markedly from the 0.9 years recorded at the end of 2021 but still within the historical range. NAV grew as well, largely driven by the reluctance of managers to exit positions and crystallize returns in a depressed multiple environment.

Private equity strategies diverged

Buyout and venture capital, the two largest PE sub-asset classes, charted wildly different courses over the past 18 months. Buyout notched its highest fundraising year ever in 2023, and its performance improved, with funds posting a (still paltry) 5 percent net internal rate of return through September 30. And although buyout deal volumes declined by 19 percent, 2023 was still the third-most-active year on record. In contrast, venture capital (VC) fundraising declined by nearly 60 percent, equaling its lowest total since 2015, and deal volume fell by 36 percent to the lowest level since 2019. VC funds returned –3 percent through September, posting negative returns for seven consecutive quarters. VC was the fastest-growing—as well as the highest-performing—PE strategy by a significant margin from 2010 to 2022, but investors appear to be reevaluating their approach in the current environment.

Private equity entry multiples contracted

PE buyout entry multiples declined by roughly one turn from 11.9 to 11.0 times EBITDA, slightly outpacing the decline in public market multiples (down from 12.1 to 11.3 times EBITDA), through the first nine months of 2023. For nearly a decade leading up to 2022, managers consistently sold assets into a higher-multiple environment than that in which they had bought those assets, providing a substantial performance tailwind for the industry. Nowhere has this been truer than in technology. After experiencing more than eight turns of multiple expansion from 2009 to 2021 (the most of any sector), technology multiples have declined by nearly three turns in the past two years, 50 percent more than in any other sector. Overall, roughly two-thirds of the total return for buyout deals that were entered in 2010 or later and exited in 2021 or before can be attributed to market multiple expansion and leverage. Now, with falling multiples and higher financing costs, revenue growth and margin expansion are taking center stage for GPs.

Real estate receded

Demand uncertainty, slowing rent growth, and elevated financing costs drove cap rates higher and made price discovery challenging, all of which weighed on deal volume, fundraising, and investment performance. Global closed-end fundraising declined 34 percent year over year, and funds returned −4 percent in the first nine months of the year, losing money for the first time since the 2007–08 global financial crisis. Capital shifted away from core and core-plus strategies as investors sought liquidity via redemptions in open-end vehicles, from which net outflows reached their highest level in at least two decades. Opportunistic strategies benefited from this shift, with investors focusing on capital appreciation over income generation in a market where alternative sources of yield have grown more attractive. Rising interest rates widened bid–ask spreads and impaired deal volume across food groups, including in what were formerly hot sectors: multifamily and industrial.

Private debt pays dividends

Debt again proved to be the most resilient private asset class against a turbulent market backdrop. Fundraising declined just 13 percent, largely driven by lower commitments to direct lending strategies, for which a slower PE deal environment has made capital deployment challenging. The asset class also posted the highest returns among all private asset classes through September 30. Many private debt securities are tied to floating rates, which enhance returns in a rising-rate environment. Thus far, managers appear to have successfully navigated the rising incidence of default and distress exhibited across the broader leveraged-lending market. Although direct lending deal volume declined from 2022, private lenders financed an all-time high 59 percent of leveraged buyout transactions last year and are now expanding into additional strategies to drive the next era of growth.

Infrastructure took a detour

After several years of robust growth and strong performance, infrastructure and natural resources fundraising declined by 53 percent to the lowest total since 2013. Supply-side timing is partially to blame: five of the seven largest infrastructure managers closed a flagship vehicle in 2021 or 2022, and none of those five held a final close last year. As in real estate, investors shied away from core and core-plus investments in a higher-yield environment. Yet there are reasons to believe infrastructure’s growth will bounce back. Limited partners (LPs) surveyed by McKinsey remain bullish on their deployment to the asset class, and at least a dozen vehicles targeting more than $10 billion were actively fundraising as of the end of 2023. Multiple recent acquisitions of large infrastructure GPs by global multi-asset-class managers also indicate marketwide conviction in the asset class’s potential.

Private markets still have work to do on diversity

Private markets firms are slowly improving their representation of females (up two percentage points over the prior year) and ethnic and racial minorities (up one percentage point). On some diversity metrics, including entry-level representation of women, private markets now compare favorably with corporate America. Yet broad-based parity remains elusive and too slow in the making. Ethnic, racial, and gender imbalances are particularly stark across more influential investing roles and senior positions. In fact, McKinsey’s research  reveals that at the current pace, it would take several decades for private markets firms to reach gender parity at senior levels. Increasing representation across all levels will require managers to take fresh approaches to hiring, retention, and promotion.

Artificial intelligence generating excitement

The transformative potential of generative AI was perhaps 2023’s hottest topic (beyond Taylor Swift). Private markets players are excited about the potential for the technology to optimize their approach to thesis generation, deal sourcing, investment due diligence, and portfolio performance, among other areas. While the technology is still nascent and few GPs can boast scaled implementations, pilot programs are already in flight across the industry, particularly within portfolio companies. Adoption seems nearly certain to accelerate throughout 2024.

Private markets in a slower era

If private markets investors entered 2023 hoping for a return to the heady days of 2021, they likely left the year disappointed. Many of the headwinds that emerged in the latter half of 2022 persisted throughout the year, pressuring fundraising, dealmaking, and performance. Inflation moderated somewhat over the course of the year but remained stubbornly elevated by recent historical standards. Interest rates started high and rose higher, increasing the cost of financing. A reinvigorated public equity market recovered most of 2022’s losses but did little to resolve the valuation uncertainty private market investors have faced for the past 18 months.

Within private markets, the denominator effect remained in play, despite the public market recovery, as the numerator continued to expand. An activity-dampening cycle emerged: higher cost of capital and lower multiples limited the ability or willingness of general partners (GPs) to exit positions; fewer exits, coupled with continuing capital calls, pushed LP allocations higher, thereby limiting their ability or willingness to make new commitments. These conditions weighed on managers’ ability to fundraise. Based on data reported as of year-end 2023, private markets fundraising fell 22 percent from the prior year to just over $1 trillion, the largest such drop since 2009 (Exhibit 1).

The impact of the fundraising environment was not felt equally among GPs. Continuing a trend that emerged in 2022, and consistent with prior downturns in fundraising, LPs favored larger vehicles and the scaled GPs that typically manage them. Smaller and newer managers struggled, and the number of sub–$1 billion vehicles and new firm launches each declined to its lowest level in more than a decade.

Despite the decline in fundraising, private markets assets under management (AUM) continued to grow, increasing 12 percent to $13.1 trillion as of June 30, 2023. 2023 fundraising was still the sixth-highest annual haul on record, pushing dry powder higher, while the slowdown in deal making limited distributions.

Investment performance across private market asset classes fell short of historical averages. Private equity (PE) got back in the black but generated the lowest annual performance in the past 15 years, excluding 2022. Closed-end real estate produced negative returns for the first time since 2009, as capitalization (cap) rates expanded across sectors and rent growth dissipated in formerly hot sectors, including multifamily and industrial. The performance of infrastructure funds was less than half of its long-term average and even further below the double-digit returns generated in 2021 and 2022. Private debt was the standout performer (if there was one), outperforming all other private asset classes and illustrating the asset class’s countercyclical appeal.

Private equity down but not out

Higher financing costs, lower multiples, and an uncertain macroeconomic environment created a challenging backdrop for private equity managers in 2023. Fundraising declined for the second year in a row, falling 15 percent to $649 billion, as LPs grappled with the denominator effect and a slowdown in distributions. Managers were on the fundraising trail longer to raise this capital: funds that closed in 2023 were open for a record-high average of 20.1 months, notably longer than 18.7 months in 2022 and 14.1 months in 2018. VC and growth equity strategies led the decline, dropping to their lowest level of cumulative capital raised since 2015. Fundraising in Asia fell for the fourth year of the last five, with the greatest decline in China.

Despite the difficult fundraising context, a subset of strategies and managers prevailed. Buyout managers collectively had their best fundraising year on record, raising more than $400 billion. Fundraising in Europe surged by more than 50 percent, resulting in the region’s biggest haul ever. The largest managers raised an outsized share of the total for a second consecutive year, making 2023 the most concentrated fundraising year of the last decade (Exhibit 2).

Despite the drop in aggregate fundraising, PE assets under management increased 8 percent to $8.2 trillion. Only a small part of this growth was performance driven: PE funds produced a net IRR of just 2.5 percent through September 30, 2023. Buyouts and growth equity generated positive returns, while VC lost money. PE performance, dating back to the beginning of 2022, remains negative, highlighting the difficulty of generating attractive investment returns in a higher interest rate and lower multiple environment. As PE managers devise value creation strategies to improve performance, their focus includes ensuring operating efficiency and profitability of their portfolio companies.

Deal activity volume and count fell sharply, by 21 percent and 24 percent, respectively, which continued the slower pace set in the second half of 2022. Sponsors largely opted to hold assets longer rather than lock in underwhelming returns. While higher financing costs and valuation mismatches weighed on overall deal activity, certain types of M&A gained share. Add-on deals, for example, accounted for a record 46 percent of total buyout deal volume last year.

Real estate recedes

For real estate, 2023 was a year of transition, characterized by a litany of new and familiar challenges. Pandemic-driven demand issues continued, while elevated financing costs, expanding cap rates, and valuation uncertainty weighed on commercial real estate deal volumes, fundraising, and investment performance.

Managers faced one of the toughest fundraising environments in many years. Global closed-end fundraising declined 34 percent to $125 billion. While fundraising challenges were widespread, they were not ubiquitous across strategies. Dollars continued to shift to large, multi-asset class platforms, with the top five managers accounting for 37 percent of aggregate closed-end real estate fundraising. In April, the largest real estate fund ever raised closed on a record $30 billion.

Capital shifted away from core and core-plus strategies as investors sought liquidity through redemptions in open-end vehicles and reduced gross contributions to the lowest level since 2009. Opportunistic strategies benefited from this shift, as investors turned their attention toward capital appreciation over income generation in a market where alternative sources of yield have grown more attractive.

In the United States, for instance, open-end funds, as represented by the National Council of Real Estate Investment Fiduciaries Fund Index—Open-End Equity (NFI-OE), recorded $13 billion in net outflows in 2023, reversing the trend of positive net inflows throughout the 2010s. The negative flows mainly reflected $9 billion in core outflows, with core-plus funds accounting for the remaining outflows, which reversed a 20-year run of net inflows.

As a result, the NAV in US open-end funds fell roughly 16 percent year over year. Meanwhile, global assets under management in closed-end funds reached a new peak of $1.7 trillion as of June 2023, growing 14 percent between June 2022 and June 2023.

Real estate underperformed historical averages in 2023, as previously high-performing multifamily and industrial sectors joined office in producing negative returns caused by slowing demand growth and cap rate expansion. Closed-end funds generated a pooled net IRR of −3.5 percent in the first nine months of 2023, losing money for the first time since the global financial crisis. The lone bright spot among major sectors was hospitality, which—thanks to a rush of postpandemic travel—returned 10.3 percent in 2023. 2 Based on NCREIFs NPI index. Hotels represent 1 percent of total properties in the index. As a whole, the average pooled lifetime net IRRs for closed-end real estate funds from 2011–20 vintages remained around historical levels (9.8 percent).

Global deal volume declined 47 percent in 2023 to reach a ten-year low of $650 billion, driven by widening bid–ask spreads amid valuation uncertainty and higher costs of financing (Exhibit 3). 3 CBRE, Real Capital Analytics Deal flow in the office sector remained depressed, partly as a result of continued uncertainty in the demand for space in a hybrid working world.

During a turbulent year for private markets, private debt was a relative bright spot, topping private markets asset classes in terms of fundraising growth, AUM growth, and performance.

Fundraising for private debt declined just 13 percent year over year, nearly ten percentage points less than the private markets overall. Despite the decline in fundraising, AUM surged 27 percent to $1.7 trillion. And private debt posted the highest investment returns of any private asset class through the first three quarters of 2023.

Private debt’s risk/return characteristics are well suited to the current environment. With interest rates at their highest in more than a decade, current yields in the asset class have grown more attractive on both an absolute and relative basis, particularly if higher rates sustain and put downward pressure on equity returns (Exhibit 4). The built-in security derived from debt’s privileged position in the capital structure, moreover, appeals to investors that are wary of market volatility and valuation uncertainty.

Direct lending continued to be the largest strategy in 2023, with fundraising for the mostly-senior-debt strategy accounting for almost half of the asset class’s total haul (despite declining from the previous year). Separately, mezzanine debt fundraising hit a new high, thanks to the closings of three of the largest funds ever raised in the strategy.

Over the longer term, growth in private debt has largely been driven by institutional investors rotating out of traditional fixed income in favor of private alternatives. Despite this growth in commitments, LPs remain underweight in this asset class relative to their targets. In fact, the allocation gap has only grown wider in recent years, a sharp contrast to other private asset classes, for which LPs’ current allocations exceed their targets on average. According to data from CEM Benchmarking, the private debt allocation gap now stands at 1.4 percent, which means that, in aggregate, investors must commit hundreds of billions in net new capital to the asset class just to reach current targets.

Private debt was not completely immune to the macroeconomic conditions last year, however. Fundraising declined for the second consecutive year and now sits 23 percent below 2021’s peak. Furthermore, though private lenders took share in 2023 from other capital sources, overall deal volumes also declined for the second year in a row. The drop was largely driven by a less active PE deal environment: private debt is predominantly used to finance PE-backed companies, though managers are increasingly diversifying their origination capabilities to include a broad new range of companies and asset types.

Infrastructure and natural resources take a detour

For infrastructure and natural resources fundraising, 2023 was an exceptionally challenging year. Aggregate capital raised declined 53 percent year over year to $82 billion, the lowest annual total since 2013. The size of the drop is particularly surprising in light of infrastructure’s recent momentum. The asset class had set fundraising records in four of the previous five years, and infrastructure is often considered an attractive investment in uncertain markets.

While there is little doubt that the broader fundraising headwinds discussed elsewhere in this report affected infrastructure and natural resources fundraising last year, dynamics specific to the asset class were at play as well. One issue was supply-side timing: nine of the ten largest infrastructure GPs did not close a flagship fund in 2023. Second was the migration of investor dollars away from core and core-plus investments, which have historically accounted for the bulk of infrastructure fundraising, in a higher rate environment.

The asset class had some notable bright spots last year. Fundraising for higher-returning opportunistic strategies more than doubled the prior year’s total (Exhibit 5). AUM grew 18 percent, reaching a new high of $1.5 trillion. Infrastructure funds returned a net IRR of 3.4 percent in 2023; this was below historical averages but still the second-best return among private asset classes. And as was the case in other asset classes, investors concentrated commitments in larger funds and managers in 2023, including in the largest infrastructure fund ever raised.

The outlook for the asset class, moreover, remains positive. Funds targeting a record amount of capital were in the market at year-end, providing a robust foundation for fundraising in 2024 and 2025. A recent spate of infrastructure GP acquisitions signal multi-asset managers’ long-term conviction in the asset class, despite short-term headwinds. Global megatrends like decarbonization and digitization, as well as revolutions in energy and mobility, have spurred new infrastructure investment opportunities around the world, particularly for value-oriented investors that are willing to take on more risk.

Private markets make measured progress in DEI

Diversity, equity, and inclusion (DEI) has become an important part of the fundraising, talent, and investing landscape for private market participants. Encouragingly, incremental progress has been made in recent years, including more diverse talent being brought to entry-level positions, investing roles, and investment committees. The scope of DEI metrics provided to institutional investors during fundraising has also increased in recent years: more than half of PE firms now provide data across investing teams, portfolio company boards, and portfolio company management (versus investment team data only). 4 “ The state of diversity in global private markets: 2023 ,” McKinsey, August 22, 2023.

In 2023, McKinsey surveyed 66 global private markets firms that collectively employ more than 60,000 people for the second annual State of diversity in global private markets report. 5 “ The state of diversity in global private markets: 2023 ,” McKinsey, August 22, 2023. The research offers insight into the representation of women and ethnic and racial minorities in private investing as of year-end 2022. In this chapter, we discuss where the numbers stand and how firms can bring a more diverse set of perspectives to the table.

The statistics indicate signs of modest advancement. Overall representation of women in private markets increased two percentage points to 35 percent, and ethnic and racial minorities increased one percentage point to 30 percent (Exhibit 6). Entry-level positions have nearly reached gender parity, with female representation at 48 percent. The share of women holding C-suite roles globally increased 3 percentage points, while the share of people from ethnic and racial minorities in investment committees increased 9 percentage points. There is growing evidence that external hiring is gradually helping close the diversity gap, especially at senior levels. For example, 33 percent of external hires at the managing director level were ethnic or racial minorities, higher than their existing representation level (19 percent).

Yet, the scope of the challenge remains substantial. Women and minorities continue to be underrepresented in senior positions and investing roles. They also experience uneven rates of progress due to lower promotion and higher attrition rates, particularly at smaller firms. Firms are also navigating an increasingly polarized workplace today, with additional scrutiny and a growing number of lawsuits against corporate diversity and inclusion programs, particularly in the US, which threatens to impact the industry’s pace of progress.

Fredrik Dahlqvist is a senior partner in McKinsey’s Stockholm office; Alastair Green  is a senior partner in the Washington, DC, office, where Paul Maia and Alexandra Nee  are partners; David Quigley  is a senior partner in the New York office, where Connor Mangan is an associate partner and Aditya Sanghvi  is a senior partner; Rahel Schneider is an associate partner in the Bay Area office; John Spivey is a partner in the Charlotte office; and Brian Vickery  is a partner in the Boston office.

The authors wish to thank Jonathan Christy, Louis Dufau, Vaibhav Gujral, Graham Healy-Day, Laura Johnson, Ryan Luby, Tripp Norton, Alastair Rami, Henri Torbey, and Alex Wolkomir for their contributions

The authors would also like to thank CEM Benchmarking and the StepStone Group for their partnership in this year's report.

This article was edited by Arshiya Khullar, an editor in the Gurugram office.

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