A massive Danish study found only 80% natural protection from SARS-CoV-2 reinfection in general, declining to 47% in the elderly, reports MedicalBrief. A commentary in The Lancet says the “sobering” and “relatively alarming” study reinforces the case for mass immunisation programmes.
Last year, more than 10m PCR tests were performed in Denmark – 4m Danes had at least one test done. Researchers at the Statens Serum Institut (SSI) have now analysed patterns in these test data with a focus on the individuals who tested positive more than once. The data were used to estimate the degree of protection against a new infection after a past infection.
In the analysis, the researchers identified those who were tested by PCR in the first epidemic wave in the spring and looked at their test results, if any, during the second wave in the autumn and winter of 2020. The analysis showed that among those who tested positive during the first wave, 0.65% tested positive again during the second wave. By comparison, 3.3% of those who tested negative in the first wave had a positive test during the second wave. Those who had not previously tested positive were thus roughly five times more likely to test positive later on. This corresponded to an 80.5% degree of protection against a later infection.
There was no difference in protection between males and females. There was also no difference between the first part and the last part of the study period. That is, there was no sign that protection began to wane after six months. However, when dividing the population into age groups, a different pattern emerged for the senior age group. Among those aged 65 years and above, the protection was estimated to be just 47%.
“We estimated protection after natural infection to be 80% in the population overall. But we also saw that this figure, what we may call the observed immunity, was markedly lower in the older age segment, being just 50% or lower.” said senior researcher Steen Ethelberg who together with colleagues from the SSI conducted the study. Ethelberg continued:
“Our study suggests that most people will be protected from being infected again for at least half a year. But not everyone is protected and especially among the elderly, only about half appeared to be protected after a first infection. Even if you have already been infected, our findings suggest that it is advisable to keep following the general advice on how to protect yourself from infection. Furthermore, the findings highlight the need to vaccinate all, since natural protection – especially among the elderly – cannot be relied upon."
Study details
Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study
Christian Holm Hansen, Daniela Michlmayr, Sophie Madeleine Gubbels, Kåre Mølbak, Steen Ethelberg
Published in The Lancet on 17 March 2021
Abstract
Background
The degree to which infection with SARS-CoV-2 confers protection towards subsequent reinfection is not well described. In 2020, as part of Denmark's extensive, free-of-charge PCR-testing strategy, approximately 4 million individuals (69% of the population) underwent 10·6 million tests. Using these national PCR-test data from 2020, we estimated protection towards repeat infection with SARS-CoV-2.
Methods
In this population-level observational study, we collected individual-level data on patients who had been tested in Denmark in 2020 from the Danish Microbiology Database and analysed infection rates during the second surge of the COVID-19 epidemic, from Sept 1 to Dec 31, 2020, by comparison of infection rates between individuals with positive and negative PCR tests during the first surge (March to May, 2020). For the main analysis, we excluded people who tested positive for the first time between the two surges and those who died before the second surge. We did an alternative cohort analysis, in which we compared infection rates throughout the year between those with and without a previous confirmed infection at least 3 months earlier, irrespective of date. We also investigated whether differences were found by age group, sex, and time since infection in the alternative cohort analysis. We calculated rate ratios (RRs) adjusted for potential confounders and estimated protection against repeat infection as 1 – RR.
Findings
During the first surge (ie, before June, 2020), 533 381 people were tested, of whom 11 727 (2·20%) were PCR positive, and 525 339 were eligible for follow-up in the second surge, of whom 11 068 (2·11%) had tested positive during the first surge. Among eligible PCR-positive individuals from the first surge of the epidemic, 72 (0·65% [95% CI 0·51–0·82]) tested positive again during the second surge compared with 16 819 (3·27% [3·22–3·32]) of 514 271 who tested negative during the first surge (adjusted RR 0·195 [95% CI 0·155–0·246]). Protection against repeat infection was 80·5% (95% CI 75·4–84·5). The alternative cohort analysis gave similar estimates (adjusted RR 0·212 [0·179–0·251], estimated protection 78·8% [74·9–82·1]). In the alternative cohort analysis, among those aged 65 years and older, observed protection against repeat infection was 47·1% (95% CI 24·7–62·8). We found no difference in estimated protection against repeat infection by sex (male 78·4% [72·1–83·2] vs female 79·1% [73·9–83·3]) or evidence of waning protection over time (3–6 months of follow-up 79·3% [74·4–83·3] vs ≥7 months of follow-up 77·7% [70·9–82·9]).
Interpretation
Our findings could inform decisions on which groups should be vaccinated and advocate for vaccination of previously infected individuals because natural protection, especially among older people, cannot be relied on.
Funding
None.
The Guardian reports that Professor Rosemary Boyton and Professor Daniel Altmann, from Imperial College London, say in a commentary that the findings are sobering because case reports have previously suggested that re-infection is extremely rare. In that light, “many will find the data reported … about protection through natural infection relatively alarming,” they write. “Only 80% protection from re-infection in general, decreasing to 47% in people aged 65 years and older are more concerning figures than offered by previous studies.”
They say the study reinforces the case for mass immunisation programmes – to include those who have contracted COVID in the past.
“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,” they write.
The Lancet commentary:
Since the start of the COVID-19 pandemic, the question of potential reinfection has been ever present. Although there has been much debate about potential reliance on herd immunity through natural infection, human coronaviruses are well adapted to subvert immunity and reinfection occurs for seasonal coronaviruses that cause the common cold due to ephemeral immunity that is poorly protective between infections.
Furthermore, detailed mapping of immune parameters in cohorts such as health-care workers emphasises the heterogeneity of immune responsiveness to SARS-CoV-2, from those with high neutralising antibody titres and broad T-cell repertoires, to the minority with barely detectable immunity.
These very low levels of immunity after infection would be hard to equate with protection from reinfection. Furthermore, among the longitudinal studies that have investigated waning antibody levels against SARS-CoV-2, responses have been found to last for 6 months or longer; although, depending on which components of the antibody repertoire are assayed, a substantial minority serorevert to negativity.
Despite the substantial advances in all aspects of COVID-19 analysis and data collection over the past year, calculation of the risk of reinfection has been difficult and there are two key reasons for this. The most obvious reason for difficulty is that most individuals around the world who became infected during the first wave of the pandemic did not access a PCR or antibody test and were not admitted to or treated in hospital, and so are not included in many COVID-19 datasets. The second reason is that scientific journals require specific evidence for formal reporting of reinfection, leading to probable under-reporting. For instance, peer reviewers and editors have required evidence from individuals who tested positive by PCR, then recovered and became negative by PCR, and then subsequently tested positive by a second PCR test, with distinct sequenced viral isolates on each occasion.
Outside of a research cohort setting, such evidence gathering is rarely achievable and potential confounders exist to reinfection analysis. For example, a minority of individuals can harbour a reservoir of persistent SARS-CoV-2 in the gut, such that distinguishing between true reinfection as opposed to recurrence of the original infection is challenging. A study of health-care workers in Sergipe, Brazil, indicated a relatively high rate of reinfections correlated with the lowest antibody responses, but in most cases the researchers could not confirm de-novo reinfection. From that study, the investigators estimated risk of reinfection to be approximately 7%.
In The Lancet, Christian Hansen and colleagues report their population study of a Danish cohort investigating the risk of becoming positive for SARS-CoV-2 by PCR for the second time, presumed to indicate reinfection.
The study makes use of data from Denmark's national PCR-testing strategy whereby approximately 4 million people took 10·6 million PCR tests. Because the data in the system were person-identifiable, the authors were able to determine that 3·27% of those who were uninfected during the first surge had a positive test during the second surge, compared with 0·65% among those who had previously recorded a positive test. Thus, they determined from that, in general, past infection confers 80·5% protection against reinfection, which decreases to 47·1% in those aged 65 years and older. Hansen and colleagues acknowledge the many limitations of their analysis being restricted to only PCR data, including the possibility that people might change their behaviour after a positive PCR test. This confounder is addressed by noting that the findings are similar in a sensitivity analysis of nurses, doctors, social workers, and health-care assistants who were tested regularly due to their profession.
Set against the more formal reinfection case reports that are based on differential virus sequence data and make reinfection appear an extremely rare event, many will find the data reported by Hansen and colleagues about protection through natural infection relatively alarming. Only 80·5% protection from reinfection in general, decreasing to 47·1% in people aged 65 years and older are more concerning figures than offered by previous studies. Until now, one of the largest datasets has come from Qatar during a period of high disease burden and reported an estimated reinfection risk of 0·2%.
However, a key difference between the studies is that the Danish study is based on a universally accessible national testing programme for both symptomatic and non-symptomatic individuals, whereas the Qatar data are derived from a programme of PCR testing in the context of symptomatic disease. PCR-positive cases within the Danish dataset are thus likely to encompass a far higher proportion of asymptomatic cases presumed to elicit more marginal levels of protective immunity.
The quality, quantity, and durability of protective immunity elicited by natural infection with SARS-CoV-2 are poor relative to the much higher levels of virus-neutralising antibodies and T cells induced by the vaccines currently being administered globally. Emergence of variants of SARS-CoV-2 with variable escape from natural and vaccine-induced immunity complicates matters further. Precise correlates of protection against SARS-CoV-2 are not known, but emerging variants of concern might shift immunity below a protective margin, prompting the need for updated vaccines. Interestingly, vaccine responses even after single dose are substantially enhanced in individuals with a history of infection with SARS-CoV-2.
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.
[link url="https://en.ssi.dk/news/news/2021/new-study-estimates_have-been-infected-are-protected-against-becoming-infected-again"]Statens Serum Institut (SSI) material[/link]
[link url="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00575-4/fulltext"]The Lancet study (Open access)[/link]
[link url="https://www.theguardian.com/world/2021/mar/17/older-people-more-likely-to-catch-covid-a-second-time"]Full report in The Guardian (Open access)[/link]
[link url="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00662-0/fulltext"]The Lancet comment (Open access)[/link]