Quantifying the risk of SARS‐CoV‐2 reinfection over time

Summary Despite over 140 million SARS‐CoV‐2 infections worldwide since the beginning of the pandemic, relatively few confirmed cases of SARS‐CoV‐2 reinfection have been reported. While immunity from SARS‐CoV‐2 infection is probable, at least in the short term, few studies have quantified the reinfection risk. To our knowledge, this is the first systematic review to synthesise the evidence on the risk of SARS‐CoV‐2 reinfection over time. A standardised protocol was employed, based on Cochrane methodology. Electronic databases and preprint servers were searched from 1 January 2020 to 19 February 2021. Eleven large cohort studies were identified that estimated the risk of SARS‐CoV‐2 reinfection over time, including three that enrolled healthcare workers and two that enrolled residents and staff of elderly care homes. Across studies, the total number of PCR‐positive or antibody‐positive participants at baseline was 615,777, and the maximum duration of follow‐up was more than 10 months in three studies. Reinfection was an uncommon event (absolute rate 0%–1.1%), with no study reporting an increase in the risk of reinfection over time. Only one study estimated the population‐level risk of reinfection based on whole genome sequencing in a subset of patients; the estimated risk was low (0.1% [95% CI: 0.08–0.11%]) with no evidence of waning immunity for up to 7 months following primary infection. These data suggest that naturally acquired SARS‐CoV‐2 immunity does not wane for at least 10 months post‐infection. However, the applicability of these studies to new variants or to vaccine‐induced immunity remains uncertain.

SARS-CoV-2 infection. These reviews arose directly from questions posed by policy makers and expert clinicians supporting the National Public Health Emergency Team to inform the national response to the pandemic in Ireland.
Our team at HIQA previously concluded that SARS-CoV-2 infection produces detectable immune responses in most cases. 1 However, the extent to which previously infected people are immune to reinfection is uncertain. In the short term, protection against reinfection is probable, as few confirmed SARS-CoV-2 reinfections have been reported despite over 140 million infections worldwide since the beginning of the pandemic. 2 The objective of this systematic review was to evaluate the risk and relative risk of SARS-CoV-2 reinfection over time, comparing previously infected individuals to those without evidence of prior infection. The review informed a range of policy questions relating to the duration of protective immunity (as in, prevention of reinfection) following SARS-CoV-2 infection.

| METHODS
A standardised protocol was employed 3 based on Cochrane methodology. 4 Electronic databases (PubMed, EMBASE and EuropePMC) were searched from 1 January 2020 to 19 February 2021 (Data S1). Reinfection was defined as any reverse transcription polymerase chain reaction (RT-PCR) or antigen-confirmed SARS-CoV-2 infection in an individual with evidence of a prior SARS-CoV-2 infection. Evidence of prior infection included a previously documented immune response through antibody detection (seropositivity) and/or a prior SARS-CoV-2 diagnosis by RT-PCR or antigen testing followed by recovery (molecular or clinical evidence of viral clearance). No minimum time interval was defined between primary and secondary infections; however, cases within 90 days of initial infection were considered suggestive of prolonged viral shedding following the primary infection.
All potentially eligible papers, including preprints, were exported to Endnote x8.2 and screened for relevance by one reviewer.
Following removal of irrelevant citations, two reviewers independently reviewed the full text of potentially relevant articles. For each included study, data on study design, participant demographics and relevant clinical and laboratory data were extracted by two reviewers. Quality appraisal was undertaken using the National Heart, Lung and Blood Institute (NIH) quality assessment tool for observational cohort studies. 6 The findings of the research question were synthesised narratively due to the heterogeneity of study designs and outcome data.

| RESULTS
The collective database search resulted in 1893 citations, with four citations retrieved from other sources (grey literature search).  (Table S1).
The median follow-up of individuals within studies was 131 days (4.4 months; range of medians: 54-210 days), with a maximum followup of ≥300 days (10 months) in three studies. 12,14,16 Studies reported a range of primary endpoints (Table 2 and Table S2). Studies either determined evidence of prior infection based on a history of RT-PCR confirmed infection (n = 5 studies), 10,12,[15][16][17] documented antibody detection (n = 4 studies) 7,8,11,14 or a combination of both (n = 2 studies). 9,13 Three studies separately reported the relative risks of symptomatic reinfections and 'all' reinfections (symptomatic/asymptomatic), 8,11,15 one study reported symptomatic reinfections only 9 and the remaining studies did not differentiate between symptomatic and asymptomatic reinfections. 7,10,[12][13][14][15][16][17] In addition to quantifying the absolute risks of SARS-CoV-2 reinfection, the risks compared with PCR-negative or antibody-negative cohorts at baseline were expressed by a number of different measures, such as relative risks, odds ratios, risk ratios and hazard ratios. Due to heterogeneity in outcome measures and populations, meta-analysis of data were not considered appropriate. The following sections narratively report the findings of included studies by population group (general population, healthcare workers, and residents and staff of care homes).

| Austria
In the study by Pilz et al., 16 national SARS-CoV-2 infection data from the Austrian epidemiological reporting system were used to investigate potential reinfection events, with a maximum follow-up of

| Denmark
In the study by Hansen et al., 17  Abbreviations: aHR, adjusted hazard ratio; aOR, adjusted odds ratio (adjusted for week group); ARR, adjusted rate ratio; CI, confidence interval; f/u, follow-up; HCW, healthcare worker; IRR, incidence rate ratio; NAAT, nucleic acid amplification test; WGS, whole genome sequencing.   In the second, 150,325 patients were followed for a maximum of

| Healthcare workers
Three UK studies were identified that exclusively enrolled healthcare workers. In the first study, published as a preprint, 20,787 hospital staff were followed, of whom 32% (n = 6614) were assigned to the positive cohort (antibody or PCR positive) and 68% (n = 14,173) to the negative cohort (antibody negative, not previously known to be PCR

| Residents and staff of elderly care homes
Two studies were identified that enrolled both residents and staff at UK care homes. 13 In the first study (Jeffery-Smith et al. 13 ), the risk of reinfection according to antibody seropositivity was investigated following outbreaks in two London care homes 13

| Quality of included studies
The NIH quality assessment tools was used for appraisal of observational cohort studies. 6 Ten studies were considered of 'good' or 'fair' methodological quality (Table S3), with one study 10 that used a proxy measure for outcomes (NAAT test positivity) considered to be of poor quality.
Each of the 10 studies of 'good' (n = 4) or 'fair' (n = 6) methodological quality was considered large enough to adequately capture reinfection events in their respective populations. A number of studies was downgraded due to lack of controlling for confounders (n = 7 studies). In these studies, potential confounding variables were either not assessed or not measured appropriately, or the statistical analysis was not adequately described. As all studies were observational in nature, they cannot be used to demonstrate causality. Therefore, only associations between prior infection and reinfection risk can be measured. While estimates of the effectiveness of natural infection to prevent reinfection were reported in a number of studies, such measures cannot be reliably estimated on the basis of these data.
Six studies are currently published as preprints, 7,8,10,12,14,15 so have not yet been formally peer-reviewed, raising additional concerns about overall quality and the potential for results to change prior to formal publication.  (RR = 0.038; 95% CI: 0.005-0.273), and the protection against reinfection after four months in seropositive group was estimated at 96.2% (95% CI: 72.7%-99.5%). 13 This relative risk was based on a single reinfection event in a seropositive staff member, indicating the relative risk in the elderly resident cohort is even lower. The second study reported higher relative rates of reinfection 14  Three UK studies estimated the relative risk of reinfection specifically among healthcare workers. 8,9,11 The first study detected zero

| Strengths and limitations
To our knowledge, this is the first systematic review to quantify the risk of SARS-CoV-2 reinfection over time. All studies were consid- This was true for studies that accessed large databases in Austria, 16 Denmark 17 and the United States. 10 Finally, this review included a number of studies that were published as preprints (n = 6 studies 7,8,10,12,14,15 ). While preprints have been pivotal to guide policy and practice throughout this pandemic, these studies have not yet been formally peer-reviewed raising concerns over the quality and accuracy of presented data.

| Generalisability of findings
There are a number of issues relating to the applicability and generalisability of the presented results. First, all but two studies preceded the widespread identification and spread of a number of new Second, all presented data relate to unvaccinated cohorts as they preceded vaccine roll-out in 10 studies, and in the only study that was conducted during vaccine roll-out, all vaccinated individuals were excluded once 12 days had passed since their vaccination. 14 The applicability of the data to vaccinated populations is therefore unknown.
One preprint study (Lumley et  Third, there is much uncertainty in relation to the risk of reinfection in younger and older age groups. Inconsistent data were identified relating to elderly populations, with one study reporting higher rates of reinfection compared with younger age groups 17 and two reporting low rates of reinfection in elderly residents of care homes (although these two studies did not compare risk across age groups). 13 without, for up to 10 months. The relative risk of reinfection was low across studies, although there was some inconsistent evidence of a higher risk in older populations compared with younger populations.
A limitation of this review was the uncertainty regarding the applicability of data to new variants of concern and to vaccinated populations.