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Two years into the pandemic, medical scientists consider what the future may hold

Stanford Medicine scientists explain what we know, and what we don’t know, about living with COVID-19 two years after the World Health Organization declared a pandemic.

- By Krista Conger

Stanford Health Care's Claudette Johnston-Creary, RN, gives Liza Bencriscutto a COVID-19 vaccine at a clinic in Redwood City.
Nigel Walker

In the two years since the World Health Organization declared COVID-19 a pandemic, we’ve become armchair experts on genetics, virology, immunity, the circulation of aerosolized particles and the Greek-alphabet soup of coronavirus variants — alpha, beta, delta, omicron. Yet no one knows with certainty what’s on the horizon.

What does it mean for a virus to become endemic? How long does immunity from vaccination or infection last? When you wake up with a sore throat, what type of test can indicate whether you have allergies or COVID-19? Do you still need to wear a mask? And most importantly: When will this all end? 

“Right now, the virus is trying to arrive at a successful strategy,” said David Relman, MD, the Thomas C. and Joan M. Merigan Professor, professor of microbiology and immunology, and a former president of the Infectious Diseases Society of America. “Viruses just want to replicate and persist in a population, and what this virus looks like three years from now is probably still different from what it will look like in five to 10 years.” 

Since March 11, 2020, more than 6 million people have died of COVID-19, which is caused by the SARS-CoV-2 virus. In the United States alone, the death toll is approaching 1 million. Recent changes in Centers for Disease Control guidelines and waning commitment from the public on mitigation efforts like masking and distancing, coupled with a fall in hospitalizations and deaths, mean that many parts of the country are returning to business as usual in what is still a very unusual time. 

If it’s endemic, is that good?

There’s no sign the virus is going away anytime soon. Nevertheless, many of us cling to the hope that the harm it can cause will decrease — that COVID-19 will become nothing more worrisome than the common cold. This scenario is what many people think of when they hear the term endemic. 

But, in reality, endemic doesn’t mean harmless. Tuberculosis and HIV — two well-known endemic diseases — together cause millions of deaths each year around the world. Another endemic disease, influenza, not only kills hundreds of thousands of people globally each year, but it also periodically mutates to cause full-blown pandemics, like the 1918 Spanish influenza, which is estimated to have killed 50 million people worldwide. 

Endemicity is also not certain.

“An endemic relationship speaks to a degree of adaptation that allows a stable co-existence,” Relman said. “In many cases, epidemics fizzle out after a year or two if the infectious agent is unsuccessful in establishing this relationship. It’s a real crapshoot to see if SARS-CoV-2 has what it takes to adapt successfully, and we will need to watch and wait and see if this happens.”

The clinical virology lab at Stanford processed its 1 millionth PCR test for COVID-19  on Feb. 10.
Nina Valderrama-Quezada

Herd immunity — which occurs when viral transmission is effectively stopped because enough people in a population have become immune — is another hopeful term. Immunity can be achieved either by recovering from infection or by getting vaccinated against SARS-CoV-2. But that immunity appears to wane within weeks or months, leaving people susceptible to reinfection or breakthrough infections. 

“When you talk about herd immunity, you have to ask yourself what that means at a global population level,” Relman said. “Whose herd do you mean? And to what degree of immunity? The unvaccinated will eventually accumulate some degree of immunity, but we may well continue to see unequal outcomes in severe disease and deaths between vaccinated and unvaccinated people for some period of time.” 

As of early March, the Centers for Disease Control reports that 65% of the U.S. population was fully vaccinated, but only 50% of those eligible for boosters had received one. Some vaccine-hesitant people feel that immunity obtained through infection is preferable to vaccination. But becoming infected is a gamble. 

“Infection does induce immunity, and in some cases this can be long-lasting,” said Bali Pulendran, PhD, professor of microbiology and immunology and of pathology. “But no one can predict how their body will respond to infection. In some cases, infection causes severe disease that can be fatal in a small minority of people. Would you do a bungee jump if you were told that the risk of dying was 0.5%?”

Navigating COVID-19 testing 

Since the beginning of the pandemic, Stanford Medicine has been at the epicenter of diagnostic and research testing to track the spread of the virus and the way our immune systems respond to infection and vaccination. Recently, the Stanford Clinical Virology Laboratory completed its 1 millionth PCR test for SARS-CoV-2. And last week, the laboratory launched a new test to track antibody levels in infected or vaccinated people — a critical way to monitor how immunity wanes. The lab is the first among regulated clinical testing laboratories nationwide to offer the test.

“This is the same assay that was used during clinical trials of several COVID-19 vaccines, and it is calibrated to the WHO international standard,” said Benjamin Pinsky, MD, PhD, medical director of the laboratory. “Until now, assays from different companies would give varying results that are difficult to interpret. Now, we will have harmonized data that can be used to guide clinical and policy decisions.” The test is primarily being used to determine whether immunocompromised people have mounted a protective antibody response after vaccination and to identify those who may benefit from additional boosters or who are at greater risk of severe disease. 

“Of course, whether a vaccine will provide protection also depends on the degree of exposure a person has to the virus,” said Scott Boyd, MD, PhD, associate professor of pathology, who recently published a study with research scientist Katharina Röltgen and other Stanford colleagues comparing antibody responses to infection versus vaccination. “If you’re sitting 2 feet away from a highly contagious person, and neither of you is wearing a mask, you will have more exposure than if you were still masking and distancing.” 

But how do you know if you are contagious, or even infected? Pinsky cautions that although at-home rapid tests, or antigen tests, are useful, they have their limitations. 

“People need to remember that a negative result does not rule out an infection,” Pinsky said. “They are useful only when the result is positive. If the rapid test is negative, you could still be infected, and you could still transmit the virus to others. I think it’s hard for people to wrap their minds around that.” 

Rosie Flores, center, meets with Linda Geng and Hector Bonilla at Stanford's Post-Acute COVID-19 Syndrome Clinic.
Steve Fisch

Rapid tests are appropriate for people who have symptoms of COVID-19, including a fever, sore throat, runny nose and muscle aches, Boyd and Pinsky said. “If the result is positive, you have confirmed that you are infected with SARS-CoV-2,” Boyd said. “If it’s negative, and your symptoms continue, you should seek out a PCR test.” 

“Antigen tests can also be used to track the course of a known infection, and they can facilitate an earlier release from isolation and return to work,” Pinsky added. 

To mask or not to mask

Pinsky envisions a reduction in demand for at-home COVID-19 testing and a decline in availability of the tests as manufacturers are confronted with reduced demand and additional regulatory requirements from the Food and Drug Administration. 

“At some point, we’re not going to be isolating everyone who has COVID-19,” Pinsky said. “When that happens, the value of testing will be decreased if the result doesn’t affect patient management. We don’t test every person with respiratory symptoms for the flu during influenza season because for most people it wouldn’t change their care.”

As mask requirements and restrictions on gatherings have rolled back, the burden of disease prevention has fallen more squarely on those who have the most to lose — the immunocompromised and those with children too young to be vaccinated. 

“Leaving mitigation efforts up to people at high risk means they are going to need even higher levels of protection,” said Abraar Karan, MD, an infectious disease fellow at Stanford Medicine who has advocated for increased availability of high-quality N95 masks. “This is an ethically fraught position. But pragmatically it is what is happening. Unfortunately, public health decisions often run counter to health equity, which inherently means allocating more resources to the most vulnerable.” 

Even in healthy people, infection can carry significant risks. 

“I’m concerned about the long-term effects on the brain, heart and other organ systems,” said Karan, noting recent data suggesting an association between COVID-19 infection and brain inflammation and vascular effects, including erectile dysfunction. “It’s concerning that some people no longer consider infection to be a big deal.” 

Researchers at Stanford Medicine are monitoring people who have recovered from COVID-19 infection as part of the National Institutes of Health’s RECOVER Initiative to learn more about the lasting effects of the infection. Last spring, Stanford Medicine launched a clinic dedicated to helping people manage symptoms that can include fatigue, shortness of breath and cognitive dysfunction, or “brain fog.”

The long game

The trauma of the pandemic has taught us valuable lessons and reinforced some we already knew. The next pandemic won’t be a surprise, at least to infectious disease experts like Yvonne Maldonado, MD, the Taube Professor in Global Health and Infectious Diseases. “It’s not if, but when,” Maldonado said. “We’ve seen multiple outbreaks of newly emerging diseases over the past 50 years, including several other coronaviruses. It happens as predictably as lightning starting a forest fire. We are going to need to think smart and move fast.”

Airborne viruses are particularly difficult to combat. “We need long-term solutions like increased air filtration in workplaces and schools, and access to high-quality, reusable masks,” Karan said. Conditions in the developing world are even more dire. 

“Most of our mitigation efforts have been rolled out with no thought to equity whatsoever,” said Maldonado, a professor of pediatric infectious diseases and of health research and policy. “Half of all the available vaccines have gone exclusively to high-income countries, while over 75% of people in sub-Saharan Africa have little or no access to places to even wash their hands.”

Over the past two years, we have conquered so many obstacles.

Low levels of vaccination mean the virus has easy access to reservoirs of susceptible people in whom it can mutate and develop into new variants. But mutations can also happen when the virus is forced to adapt to a new challenge, such as the immunity developed after vaccination, Relman noted. “Another challenge the virus hasn’t faced much yet are the drugs we are developing to treat infection,” he said. “As we begin using oral medications that people can take outside the hospital, it wouldn’t surprise me if we see some seriously resistant variants. That doesn’t mean they will be more virulent, though, just more resistant to treatment.”

On the whole, Maldonado said, she is hopeful.  “Over the past two years, we have conquered so many obstacles. In one year we developed and approved a vaccine that is nearly 100% effective, and we have now administered nearly 11 billion doses around the world. This is a triumph. And we are going to continue to get better at making new vaccines.”

Improvements on the horizon include increased understanding about the most effective dose amounts and schedules for specific population and age groups, and new technologies and vaccine platforms that can rapidly pivot to combat new viral variants or even new viruses that might drive the next pandemic.

Even with these advances, most of us have probably have more COVID-19 vaccinations in our future. 

 “Until we learn how to enhance the durability of vaccine-induced immunity, we may very well need a booster at least annually, or perhaps even more frequently,” Pulendran said. “There will almost certainly be a COVID-29, or a COVID-50, so we will continue to keep our eyes on the ball and innovate new vaccines that are globally accessible.” 

How many more anniversaries of this pandemic will we have to commemorate? 

“I don’t know many people who think that this virus will end human civilization,” Relman said. “But everyone who latches onto the idea that the virus will fade away is forgetting that there are almost certainly going to be major bumps in the road, and those bumps could be painful. Two years is not long enough to know how this story ends.”

Stanford Medicine integrates research, medical education and health care at its three institutions - Stanford School of Medicine, Stanford Health Care, and Stanford Children's Health. For more information, please visit the Office of Communications website at http://mednews.stanford.edu.

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Understanding the world within us

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