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Older people appeared especially susceptible to COVID-19 reinfection, but neither sex nor time since previous infection made a difference in risk, a large population-based study in Denmark found.

An analysis examining data by age, sex, and time since last infection found adults ages 65 and older had 47.1% observed protection against reinfection (95% CI 24.7-62.8), reported Steen Ethelberg, PhD, of Statens Serum Institut in Copenhagen, and colleagues.

Overall observed protection against reinfection in the general population was 80.5% (95% CI 75.4%-84.5%) when comparing PCR test results from the first and second surge, the authors wrote in .

SARS-CoV-2 reinfections are rare, with only a handful of cases reported globally, as well as prior evidence suggesting immunity generally lasts up to 5-6 months following infection.

In Denmark, adults were able to get free PCR testing starting in May 2020, and this expanded to everyone age 2 and older in September 2020, for a total of more than 10 million PCR tests on almost 4 million uniquely identifiable individuals by the end of December.

The authors first analyzed infection rates from two time points to approximately the spring and fall COVID-19 surges in Denmark. The first surge was prior to June 2020, where over 533,000 people were tested. Of those, 2.2% tested positive.

Of the initial 533,000, more than 525,000 were eligible for follow-up during the second surge from Sept. 1 to Dec. 31. In this population, 2.1% of individuals had tested positive during the first surge. Of those, 72 (0.65%) tested positive again during the second surge, while 3.27% of those who were uninfected during the first surge tested positive during the second surge. That led to the figure of 80.5% for a first infection's efficacy against a second.

Ethelberg and colleagues then performed an alternative cohort analysis, examining each individual with a positive PCR test, regardless of whether or not it occurred during the second surge. All individuals with a PCR test, regardless of result, were followed until Dec. 31, 2020 or a new positive PCR test at least 90 days later.

This analysis included over 2.4 million individuals, with 2,049 contributing to both unexposed and exposed time periods, and 138 reinfections. In this analysis, estimated protection was 77.8% (95% CI 74.9%-82.1%).

Breaking out these 138 reinfections by sex, age, and time in follow-up, the authors found no significant difference in estimated protection between men and women, or time in follow-up (3-6 months vs 7 months or more), with about 77%-79% observed protection against reinfection.

However, age was a different story. While estimated protection ranged from 80%-83% among younger age groups -- 0-34, 35-49, and 50-64 -- that dropped to 47% among those 65 and older.

An by Rosemary Boyton, PhD, and Daniel Altmann, PhD, both of Imperial College London, characterized these findings as "relatively alarming," given other research showing reinfection is "a relatively rare event."

They noted the Danish program allowed symptomatic and asymptomatic individuals to receive a PCR test, meaning this data was "thus likely to encompass a far higher proportion of asymptomatic cases presumed to elicit more marginal levels of protective immunity."

"These data are all confirmation, if it were needed, that for SARS-CoV-2 the hope of protective immunity through natural infections might not be within our reach, and a global vaccination [program] with high efficacy vaccines is the enduring solution," Boyton and Altmann wrote.

Ethelberg and colleagues agreed, calling for "vaccination of previously infected individuals... because natural protection cannot be relied on."

The editorialists cited limitations to the study, however, which were also noted by study authors, including the potential that people might change their behavior after a PCR test.

"Individuals with a previous positive PCR test might engage in more high-risk activities (e.g., not wearing a face mask) because of assumed immunity, and therefore be more likely to test positive a second time," Ethelberg and colleagues wrote.

Other limitations included the fact that symptoms could not be correlated with protection against repeat infection because clinical case details were not recorded unless the patient was hospitalized with COVID-19. Misclassification, where reinfection could have been detectable virus from the first infection, was also possible.

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