COVID-19 re-infection rare, greater risk in elderly

A large observational study from Denmark has suggested that a repeat SARS-CoV-2 infection is rare following a prior infection. However, older aged individuals may be less protected following a prior SARS-CoV-2 infection than their younger counterparts.

“[W]e found that protection against repeat SARS-CoV-2 infection is robust and detectable in the majority of individuals, protecting ≥80 percent of the naturally infected population who are younger than 65 years against reinfections within the observation period,” noted the authors.

“However, we observed that individuals aged ≥65 years had <50 percent protection against repeat SARS-CoV-2 infection,” they said.

The results were based on individual-level data of the approximately 4 million individuals who underwent a total of 10.6 million PCR tests in 2020 during the nationwide free-of-charge PCR testing strategy conducted in Denmark (_^~69 percent of the population). Infection rates during the second surge of the pandemic (September–December 2020) were compared with infection rates during the first surge (March–May 2020), with inconclusive test results excluded from the analysis.

A total of 533,381 individuals underwent testing during the first surge. Of these, 2.2 percent (n=11,727) tested positive. During the second surge, 3.48 million individuals underwent testing, 4.32 percent (n=150,159) of whom tested positive. A total of 525,339 individuals were followed up during the second surge*, of whom 2.11 percent (n=11,068) had tested positive during the first surge.

Patients who tested negative during the first surge were five times more likely to test positive during the second surge than those who tested positive during the first surge (3.27 percent [n=16,819] vs 0.65 percent [n=72]; adjusted rate ratio [adjRR], 0.195, 95 percent confidence interval, 0.155–0.246 for positive vs negative test during the first surge). This rendered an estimated 80.5 percent protection against repeat infection. [Lancet 2021;397:1204-1212]

The rates were comparable in an alternative cohort analysis (n=2,432,509) which tabulated infection rates throughout the year between those with and without a previous confirmed infection ≥3 months prior regardless of date (0.48 percent [prior positive test] vs 2.2 percent [prior negative test]; adjRR, 0.212), with an estimated 78.8 percent protection against re-infection. 

In a sensitivity analysis of the 15,604 healthcare and social workers in the population who frequently underwent testing (median 10 tests each in 2020), the results were comparable to the overall results (1.2 percent [positive tests during both surges] vs 6.2 percent [negative in first surge and positive in second]; adjRR, 0.189), with an estimated 81.1 percent protection against re-infection.

“[However,] we found that the infection rate among healthcare professionals was around twice that in the general population,” the authors pointed out.

The risk of re-infection did not differ according to sex, with estimated protection rates of 78.4 and 79.1 percent in men and women, respectively (p=0.84). Protection rates also did not appear to decline over time, with rates of 79.3 and 77.7 percent at 3–6 and ≥7 months of follow-up, respectively (p=0.67).

“[W]e did not identify anything to indicate that protection against re-infection declines within 6 months of having COVID-19. The closely related coronaviruses SARS and MERS have both been shown to confer immune protection against re-infection lasting up to 3 years, but ongoing analysis of COVID-19 is needed to understand its long-term effects on patients’ chances of becoming infected again,” said study author Dr Daniela Michlmayr from the Statens Serum Institut, Copenhagen, Denmark.

 

Higher risk in the elderly

However, the alternative cohort analysis showed that protection against re-infection was notably lower in the population of individuals aged ≥65 years (47.1 percent) compared with those aged 0–34, 35–49, and 50–64 years (82.7, 80.1, and 81.3 percent, respectively).

“Our study confirms what a number of others appeared to suggest: re-infection with COVID-19 is rare in younger, healthy people, but the elderly are at greater risk of catching it again,” said study author Dr Steen Ethelberg, also from the Statens Serum Institut.

“Since older people are also more likely to experience severe disease symptoms, and sadly die, our findings make clear how important it is to implement policies to protect the elderly during the pandemic,” he said.

The authors suggested that “natural age-related changes in the immune system of older adults” may have been responsible for this reduction in protection.

“[O]ur analysis highlights the need to protect older people against reinfection with SARS-CoV-2 by vaccination, physical distancing measures, and personal protective equipment, such as facemasks, regardless of previous infection status,” they said.

 

Not time to be complacent

“Set against the more formal reinfection case reports that are based on differential virus sequence data and make re-infection appear an extremely rare event, many will find the [present] data about protection through natural infection relatively alarming. Only 80.5 percent protection from reinfection in general, decreasing to 47.1 percent in people aged ≥65 years are more concerning figures than offered by previous studies,” said Professors Rosemary Boyton and Daniel Altmann from Imperial College London, UK, in an accompanying commentary. [Lancet 2021;397:1161-1163]

“[However, these results] are … likely to encompass a far higher proportion of asymptomatic cases presumed to elicit more marginal levels of protective immunity,” they said.

The authors cautioned that the findings may not apply to more recent, and potentially more transmissible, SARS-CoV-2 variants. Furthermore, this population comprises individuals with minimal, if any, symptoms and the results may not extend to those who were hospitalized with more severe symptoms. 

“Emergence of variants of SARS-CoV-2 with variable escape from natural and vaccine-induced immunity complicates matters further,” noted Boyton and Altmann.

Furthermore, as this is a “new” disease, the length of time of protection against re-infections is yet unknown, the authors added. Further studies are required to identify the mechanisms behind immunity and their duration.

 

Vaccination remains a key prevention strategy

“Given what is at stake, the results emphasize how important it is that people adhere to measures implemented to keep themselves and others safe, even if they have already had COVID-19. Our insights could also inform policies focused on wider vaccination strategies and the easing of lockdown restrictions,” said Ethelberg.

“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 programme with high efficacy vaccines is the enduring solution,” said Boyton and Altmann.

“[V]accination of previously infected individuals should be done because natural protection cannot be relied on,” the authors concluded.