It’s clear that vaccination works. More than 9 in 10 COVID cases, hospitalizations, and deaths have occurred in people who haven’t received the vaccine. Vaccination is highly effective at preventing the most serious COVID cases, but occasionally even immunized people can develop what’s called a “breakthrough infection”—and it seems that these breakthrough infections happen more frequently with the virulent delta variant of the coronavirus.
One open question is how often breakthrough infections can lead to long COVID.
One of the most baffling aspects of the coronavirus, long COVID is an array of debilitating symptoms that can persist for weeks or months after an infection ends. Typically, these include fatigue, shortness of breath, heart palpitations, and “brain fog,” but some people develop more severe issues across multiple organs, including the lungs, heart, and brain. The problem is that there is a lack of good data around long COVID and breakthrough infections.
This dearth of data has made it impossible for most experts to state definitively that vaccinated people can develop long COVID. The Centers for Disease Control and Prevention used to track all breakthrough cases, but as of May 1 it tracks only those that lead to hospitalization and death, using data collected by state and local health agencies. This decision was made to “maximize the quality of the data collected on cases of greatest clinical and public health importance.” But without comprehensive data on breakthrough cases, it will be impossible to know the likelihood that immunized people can get infections that lead to long-lasting symptoms.
“In my opinion, CDC should be tracking all consequences of breakthrough cases, not just hospitalization and death,” Akiko Iwasaki, the Yale University immunology professor at the forefront of long COVID research, said in an email. “Even mild or asymptomatic infection can lead to long COVID. Tracking this on a national scale would be very informative.” Iwasaki is one of the only experts to have stated outright that fully vaccinated people can still get long COVID.
But again, there’s limited data to support that. Right now, there are only two published sources of data on breakthrough cases and long COVID. In a peer-reviewed study of 1,497 vaccinated health care workers in Israel, published July 29 in the New England Journal of Medicine, 39 people had breakthrough infections, 19 percent of whom reported symptoms like fatigue, headaches, and muscle pain lasting more than six weeks. Bob Wachter, chair of the University of California, San Francisco Department of Medicine, tweeted that “I’m not certain that a mild Delta breakthrough case can’t lead to long COVID,” adding that the study from Israel supports that concern.
The second source, published to the preprint server medRxiv on July 26, compiles the results of a poll on social media asking about vaccination and COVID infection. The public poll was posted to the Facebook group for Survivor Corps, a grassroots organization of COVID-19 survivors founded by Diana Berrent in March 2020. Out of 1,949 respondents, 44 reported having a symptomatic COVID-19 infection after getting vaccinated. Of that group, 24 reported they had symptoms of long COVID. One person said that their infection led to long COVID and hospitalization.
The paper, co-authored by Berrent, Yale School of Medicine cardiologist Harlan Krumholz, and postgraduate associate Daisy Massey, is not peer-reviewed, and its methods are far from rigorous; by no means should the numbers be extrapolated to apply to the general population. “I’ll be the first to say this isn’t great data,” said Berrent of the poll results. “But it’s an important signal that we need to do a better job of tracking these cases.” When Iwasaki stated on Twitter that breakthroughs could lead to long COVID, she pointed to an early version of the Survivor Corps data.
Breakthrough infections are more likely with the increasingly prevalent and highly contagious delta variant, according to an internal CDC document obtained by the New York Times, and the CDC’s latest report shows that vaccinated people can spread this variant. If breakthrough cases become more likely, and the development of long COVID is a possibility, then the U.S. must be ready for it. Right now, as the heartbreaking testimonies of people who are suffering from long COVID without meaningful treatment suggest, we are woefully unprepared.
To be very clear: The occurrence of breakthrough cases, and long COVID that may develop as a result, is not a knock on the vaccines. On the contrary, vaccination is our most potent shield against long COVID. It may not be perfect, but it prevents hospitalization and death in most cases. You can’t develop long COVID if you don’t get infected in the first place.
Estimates of the proportion of infected people who develop long COVID vary, but National Institute of Neurological Disorders and Stroke Director Walter Koroshetz points to a Nature Medicine study of 312 unvaccinated people in Bergen, Norway, with COVID-19, published in June, as the most robust approximation. Some people were hospitalized for their infection, but most isolated at home, suggesting only mild cases. After six months, 61 percent of the patients still had symptoms. Troublingly, 52 percent of people ages 16 to 30 with mild COVID-19 reported symptoms after six months.
Asked whether these numbers could translate to the U.S., Koroshetz said, “I would think so. I don’t know why it would be different.”
Koroshetz is a co-leader of the RECOVER Initiative, a massive National Institutes of Health effort to study long COVID funded by $1.15 billion set aside by Congress in December 2020. NIH Director Francis Collins announced the initiative in February, but the NIH didn’t award the first funds to institutions to “support infrastructure and core research development”—setting the stage for actual studies to take place—until June. At the time, Collins said he expected trials to launch “in the weeks and months ahead.”
The goal of RECOVER is to find treatments for people with lingering COVID-19 symptoms. To do so, scientists will first have to figure out the biological causes of long COVID, said Koroshetz. Several hypotheses already exist, and Iwasaki has proposed three: The virus might simply persist in the body after infection, causing symptoms. The “ghost” of the virus—lingering fragments like proteins and RNA—might be to blame. Or an autoimmune response is at work, triggered by the initial infection. Iwasaki says that the latter is consistent with why some fully vaccinated people still get long COVID.
“Vaccine-induced immunity is expected to clear most of the incoming virus and prevent viral spread to distal organs,” she said. “I suspect that viral reservoirs will be unlikely to be established in a fully vaccinated person. However, if the virus triggers an autoimmune response, this will lead to long-term symptoms.”
Encouragingly, research shows that vaccination can alleviate some symptoms of long COVID. Iwasaki has found that up to 30 to 40 percent of people experience relief from vaccination. It might do so by dampening the autoreactive immune cells causing symptoms, she said. She’s currently collaborating with Survivor Corps on a study of the impact of vaccination on people with long COVID, which was inspired by another of the group’s Facebook polls.
The RECOVER Initiative will be a massive undertaking, tracking people with new, acute COVID-19 infections over time as well as those who were previously infected and now have long COVID. Studies of autopsies and electronic health records will respectively shed light on the long-term damage caused by these symptoms and factors that affect recovery. The effort will eventually produce much-needed data on long COVID, but not as quickly as it’s needed.
“While the NIH sits around and does their bureaucratic thing, people are suffering and they are dying,” said Berrent.
Koroshetz recognizes the frustration of suffering patients and the doctors trying to treat them. “With the RECOVER initiative, we’ve been working constantly to launch it, and all its pieces,” he said. “I do have to apologize for how long things took to be able to move the money out into the research. It’s much faster than our usual process, but still, I have to apologize to people.”
Understanding the pathology of long COVID is necessary to develop therapeutics and diagnostics that will ultimately help prevent additional suffering and economic hardship, said Iwasaki. “There is a growing number of patients who have survived COVID-19 only to develop long-term debilitating effects like severe fatigue and cognitive dysfunction, preventing them from resuming work and living normal lives,” she added. “This is devastating millions of people around the world.”
The Survivor Corps Facebook poll on breakthrough cases and long COVID is still live and public. Right now, Berrent is focused on long COVID advocacy and convincing the CDC to mandate reporting of all breakthrough cases.
“We have to step in where nobody else is doing it, and that is ludicrous,” she said. “But if it’s necessary, then we’re here to do it.”