At least 285 individuals in Mexico appear to have contracted the novel coronavirus twice, according to a preprint posted October 18 on medRxiv. The study, which has not yet been peer reviewed, is the largest to date to assess the possibility of SARS-CoV-2 reinfection. It fuels an ongoing discussion among researchers about how long immunity to the virus lasts after an initial infection and how that length of immunity may affect the way vaccines against the virus are administered in the future.
“If we find that our immunity is poor, or nonexistent . . . this will be a big problem for vaccination policies,” study coauthor Carlos Hernandez-Suarez, a researcher at Universidad de Colima in San Sebastian, Mexico, tells The Scientist, adding that no conclusions can be made from the current data about the strength of survivors’ immunity or the protection offered by future vaccines. In his team’s analysis of hospital records of 100,432 individuals infected with SARS-CoV-2 between March and July 2020, only 285 (0.26 percent) presented signs that they’d contracted the virus twice.
Hernandez-Suarez and colleagues set out to pinpoint the frequency of reinfections among the patients. They’d read several studies pointing to possible reinfections and also an August letter to the editor in the Journal of Infection by Julian Tang, a clinical virologist at the University of Leicester in the UK, and colleagues laying out criteria for defining reinfection. The definition included an initial PCR-confirmed infection with SARS-CoV-2, then clinical recovery and a negative SARS-CoV-2 PCR test, and then a confirmed SARS-CoV-2 PCR-positive test at least 28 days after the initial positive test. The suspected second infections need to be at least 28 days after the initial ones because evidence suggests it takes that long for viral shedding to begin to taper off and because certain SARS-CoV-2 antibodies start to drop off at that point, according to another study posted to medRxiv in July.
Following that definition, Hernandez-Suarez and colleagues dug into the hospital records and identified the 285 patients obtaining medical care after a second positive PCR-confirmed SARS-CoV-2 infection. For the majority of patients, “we didn’t have the test in between,” the negative test, Hernandez-Suarez notes.
The team did have that test for 14 individuals, and it was negative, but for the rest, the patients’ second positive test came 28 days or more after the first, in some cases 60 or 70 days later, he explains. “The average was 66 days, with no complications, no problems, and then they went to the hospital again with [respiratory] problems.” To the team, that was an indication of a second infection, rather than a prolonged initial illness.
It’s hard to know without more data, such as negative tests in between positive ones, if the cases are in fact reinfections or long-lasting illnesses from a single infection, says Tang, who was not involved in the work. Still, the latest results align with other studies and case reports that indicate reinfection is rare.
“This reinfection thing is not new. It’s not unusual, not dramatic, or scary, or whatever you want to call it. It’s very normal,” Tang tells The Scientist, noting that other viruses such as respiratory syncytial virus (RSV) can cause repeated reinfections. Whether it happens frequently with SARS-CoV-2, though, he says, is not yet clear.
The genetic evidence for reinfection
The first indications that reinfection could occur came from case reports out of Hong Kong and Europe, and then Nevada. What distinguished some of these cases as clear reinfections rather than lingering initial infections is that the genomes of the viruses causing the first and second infections weren’t identical.
“You can really only prove reinfection” if the viral variants from the first and second positive swabs are different, notes Angela Rasmussen, a virologist at Columbia University in New York, “because it’s very unlikely that you would be infected with the exact same variants a second time.”
SARS-CoV-2 has an RNA genome, which has a higher mutation rate than a DNA viral genome. The mutation rate is so fast, in fact, that “even within an individual host who’s infected, you may have multiple variants that are just emerging as the virus replicates itself and makes mistakes,” she explains. The genetic changes that SARS-CoV-2 has so far accumulated seem to be functionally inconsequential, and “in the population, when you think about how many millions of different coronavirus cases there are, different variants have emerged . . . [so] it’s very unlikely that you would get the exact same one.”
A study posted September 28 to medRxiv confirms four reinfections in Qatar using genetic sequencing data that found distinct viral variants between the first and second infections. These are among 133,266 confirmed SARS-CoV-2 cases that Roberto Bertollini, a doctor with the Ministry of Public Health in Doha, and colleagues analyzed. It’s possible there were more reinfections, as the authors note that 243 individuals had positive PCR tests at least 45 days apart, but only 12 patients had sufficient viral genome data at both time points. Two of the cases had identical viral genomes on the first and second positive test, suggesting a lingering infection that never cleared in the weeks between the two positive tests, and the six others didn’t have enough genetic changes to make a firm conclusion about reinfection.
Regardless, Bertollini and his colleagues conclude in their report that “the risk for documented reinfection was very rare at about 1-2 reinfections per 10,000 infected persons.” The researchers further note that the “findings suggest that most infected persons do develop immunity against reinfection that lasts for at least [a] few months, and that reinfections (if they occur) are well tolerated and no more symptomatic than primary infections.”
Insights into immunity from reinfection cases
Contracting the virus twice within the span of a few months may be more common than the data collected so far suggest. That’s if SARS-CoV-2 acts anything like seasonal coronaviruses, according to a paper published September 14. In that study, Arthur Edridge of the University of Amsterdam and colleagues analyzed stored blood samples of 10 healthy individuals that were taken, on average, every few months for the past 35 years. The team tested the samples for an increase in antibodies to a specific region of the structural capsid protein of each seasonal coronavirus.
Antibody levels spiked and dropped at regular intervals, showing “reinfections with all four seasonal coronaviruses are common and frequently occur after about a year,” Edridge writes in an email to The Scientist. Reinfection is therefore a “common human coronavirus feature,” he explains, and SARS-CoV-2 would most likely be no exception.
Rasmussen, who was not involved with any of the studies, says that reinfection is certainly possible, but she’s less convinced that SARS-CoV-2 will act like other coronaviruses that cause colds. Those other coronavirus reinfections may happen because those viruses only cause a mild infection and don’t elicit a strong immune response with lots of long-lasting antibodies. SARS-CoV-2 could be very different, she says.
That immune durability should really be the focus of reinfection studies, Tang explains. Researchers need to look at the longevity of antibodies after infection or vaccination, because if they start to wane, then there may be a need for vaccine boosters several months after the initial shot is given. The case reports and preliminary studies contribute to that overall picture of understanding SARS-CoV-2 immunity and its implication for vaccination, he explains, “but there’s a long way to go.”