Reinfection with SARS-CoV-2 in general population, South Korea; nationwide retrospective cohort study.

To better understand the epidemiology of SARS-CoV-2 reinfections, we analyzed national data from South Korean who were followed longitudinally from January 2020 to April 2022. We conducted a nationwide retrospective cohort study to estimate possible SARS-CoV-2 reinfection rates in all residents in South Korea, with at least two episodes of laboratory-confirmed SARS-CoV-2 infection by reverse-transcriptase polymerase chain reaction or rapid antigen test (RAT) performed at least 45 or more days between both episodes, between January 2020 and April 2022. There were 16 130 855 laboratory-confirmed SARS-CoV-2 cases in South Korea, with 55 841 (346.2 per 100 000; or 0.3% of all infections) cases of possible reinfections. The reinfection rate has increased from 6.0 cases per 100 000 during Pre-Delta period to 128.0 cases per 100 000 and 355.1 cases per 100 000 during Delta and Omicron periods, respectively. Persons with one dose of vaccination had the highest reinfection rate of 642.2 per 100 000, followed by unvaccinated persons (536.2/100 000) and two-dose vaccinated persons (406.3/100 000). Our finding suggests that the majority of possible reinfections occurred following the emergence of new variants.

INTRODUCTION

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection affected >550 million individuals globally, as of July 2022. As the number of affected persons grows, concern about the duration of protection from naturally acquired immunity becomes more important, especially amidst the emergence of variants. Previous studies have suggested that reinfection of SARS‐CoV‐2 in previously infected persons is rare. In Sweden, the reinfection risk of previously SARS‐CoV‐2 infected persons was 87%–95% lower for up to 20 months. In the United States, the protection offered from prior infection ranged from 80% to 85% against infection and symptomatic infection. Of 7980 individuals monitored for 6 months in the United States, seven persons experienced reinfections after a documented first infection. However, the data from population‐based surveillance on a national scale remain scarce.

South Korea, although has relatively contained the SARS‐CoV‐2 transmission before 2022, had an increased number of infected individuals after the spread of the Omicron variant in early 2022, resulting in >18 million infected persons (out of 50 million total population), as of July 2022. COVID‐19 vaccination began since February 2021, with more than 85% of the total population having received at least one dose of vaccine, as of July 2022.

Identification of epidemiology of SARS‐CoV‐2 reinfection is important in preparing for the next emergence of variant. Currently, limited evidence concerning the SARS‐CoV‐2 reinfection is available. To better understand the epidemiology of SARS‐CoV‐2 reinfections, we analyzed national data from South Korea that were followed longitudinally from January 2020 to April 2022.

METHODS

We conducted a nationwide retrospective cohort study to estimate possible SARS‐CoV‐2 reinfection rates in all residents in South Korea, with at least two episodes of laboratory‐confirmed SARS‐CoV‐2 infection by reverse‐transcriptase polymerase chain reaction (RT‐PCR) or rapid antigen test (RAT) performed at least 45 or more days between both episodes, between January 2020 and April 2022. Our analysis was based on an integrated database from the Korea Disease Control and Prevention Agency, which collects and merges all PCR‐confirmed SARS‐CoV‐2 cases and their vaccination status, in accordance with the Infectious Disease Control and Prevention Act (Article 33‐4, 40‐5). The data included age, sex, vaccination status, and SARS‐CoV‐2 infection status.

We compare the epidemiological characteristics between all cases and reinfected cases and describe the weekly incidence of cases. Based on the national genomic surveillance, we defined the periods as follows: Pre‐Delta, from January 2020 to June 2021; Delta, from July to December 2021; and Omicron, from January to April 2022. The odds ratio (and 95% confidence interval, 1.96 (s/√n)), was estimated using conditional logistic regression.

This study was conducted as a legally mandated public health investigation under the authority of the Korean Infectious Diseases Control and Prevention Act (No. 12,444 and No. 13,392) and was not research that was subject to institutional review board approval; therefore, written informed consent was not required.

RESULTS

Between January 2020 and April 2022, there were 1 6130 855 laboratory‐confirmed SARS‐CoV‐2 cases in South Korea (Table 1). A total of 55 841 (346.2 per 100 000; or 0.3% of all infections) were cases of possible reinfections during an average observed period of 242 days (IQR; 125, 319 days). Reinfection rate has increased from 6.0 cases per 100 000 during Pre‐Delta period to 128.0 cases per 100 000 (OR, 21.38, 95% CI, 11.42–46.98; p = 0.001) and 355.1 cases per 100 000 (OR, 59.46, 95% CI, 31.94–130.12; p = 0.001) during Delta and Omicron periods, respectively. Among all age groups, children aged 0–17 yr were at the highest age‐specific rates of reinfection (470.7/100 000; OR 1.64, 95% CI 1.59–1.68, p < 0.001), followed by 18–29 years (396.5/100 000, OR 1.38, 95% CI 1.34–1.42, p < 0.001) and 30–39 years (343.8/100 000, OR 1.19, 95% CI 1.16–1.23, p < 0.001) groups. Long‐term care facility residents were at high reinfection rate of 590.5 per 100 000 (OR 1.72, 95% CI 1.64–1.8, p < 0.001). Persons with one dose of vaccination had the highest reinfection rate of 642.2 per 100 000 (OR 1.2, 95% CI, 1.13–1.27, p < 0.001), followed by unvaccinated persons (536.2/100 000, reference) and two‐dose vaccinated persons (406.3/100,000, OR 0.76, 95% CI 0.74–0.77, p < 0.001). Case fatality rates were 0.3% in all cases and 0.1% in reinfected cases.

Table 1

Characteristics of SARS‐CoV‐2 reinfected cases, January 2020–April 2022, South Korea

Characteristics	All cases		Reinfected cases				OR	95% CI	p value
	No.	(%)	No.	(%)	Rate	95% CI
Total	16 130 855		55 841		346.2	(343.3, 349.0)
Period
Pre‐Delta	133 502	(0.8)	8	(0.0)	6.0	(1.8, 10.1)	Ref.		0.001
Delta	425 883	(2.6)	545	(1.0)	128.0	(117.2, 138.7)	21.38	11.42–46.98
Omicron	15 571 470	(96.5)	55 288	(99.0)	355.1	(352.1, 358.0)	59.46	31.94–130.12
Sex
Male	7 588 561	(47.0)	26 660	(47.7)	351.3	(347.1, 355.5)	Ref.		<0.001
Female	8 542 277	(53.0)	29 181	(52.3)	341.6	(337.7, 345.5)	0.97	0.96–0.99
Age group (years)
0–17	3 808 039	(23.6)	17 926	(32.1)	470.7	(463.9, 477.6)	1.64	1.59–1.68	<0.001
18–29	2 683 865	(16.6)	10 641	(19.1)	396.5	(389.0, 404.0)	1.38	1.34–1.42
30–39	2 387 983	(14.8)	8209	(14.7)	343.8	(336.3, 351.2)	1.19	1.16–1.23
40–49	2 481 334	(15.4)	7149	(12.8)	288.1	(281.4, 294.8)	Ref.
50–59	1 969 973	(12.2)	4742	(8.5)	240.7	(233.9, 247.6)	0.84	0.80–0.87
60–74	2 052 693	(12.7)	5072	(9.1)	247.1	(240.3, 253.9)	0.86	0.83–0.89
75+	746 949	(4.6)	2102	(3.8)	281.4	(269.4, 293.4)	0.98	0.93–1.03
Status
Immunocompromised	409 697	(2.5)	1006	(1.8)	245.5	(230.4, 260.7)	0.71	0.67–0.76	<0.001
LTCF resident	307 183	(1.9)	1814	(3.2)	590.5	(563.4, 617.6)	1.72	1.64–1.8
Vaccination status
Unvaccinated	3 638 932	(22.6)	19 513	(34.9)	536.2	(528.7, 543.7)	Ref.		<0.001
1 dose	187 490	(1.2)	1204	(2.2)	642.2	(606.0, 678.3)	1.2	1.13–1.27
2 dose	4 565 171	(28.3)	18 549	(33.2)	406.3	(400.5, 412.2)	0.76	0.74–0.77
3 dose	7 705 070	(47.8)	1394	(29.4)	212.8	(209.5, 216.0)	0.40	0.39–0.40
4 dose	34 150	(0.2)	181	(0.3)	530.0	(453.0, 607.0)	0.99	0.85–1.14
Fatal cases	55 841	(0.3)	52	(0.1)	93.1	(67.8, 118.4)

Note: Symptomatic cases testing positive ≥45 days after the first infection with paired respiratory specimens; OR for status in reference to non‐immunocompromised and non‐LTCF resident; rate calculated per 100 000 persons.

Abbreviation: LTCF, long‐term care facility.

Figure 1A shows the weekly incidence of COVID‐19 cases and the percentage of reinfected case per total cases. The reinfected percentage was less than 0.1% during the Pre‐Delta period, while increased to 0.1%–0.2% during Delta Period, and 0.3% during the Omicron period. Figure 1B,C  shows the weekly incidence of the first infection of reinfected cases and the reinfection episodes. More than 2/3 of the first infection took place during the Delta period.

Figure 1

Weekly distribution of (A) total number of SARS‐CoV‐2 cases and percentage of reinfected cases; (B) first infection of reinfected cases; and (C) reinfected cases (symptomatic cases testing positive ≥45 days after the first infection with paired respiratory specimens).

DISCUSSION

We describe the epidemiology of possible SARS‐CoV‐2 reinfection in South Korea, using the national registry of COVID‐19 testing and vaccination. The possible SARS‐CoV‐2 reinfection events were rare; however, the frequency has increased following the emergence of Delta and Omicron variants in the years 2021 and 2022. Our finding is in line with results from the United States and Europe, likely due to the waning of postinfection and postvaccination immunity in the general population. , As in line with the report from France, the percentage of possible SARS‐CoV‐2 reinfection fluctuated with a higher proportion during the early phase of the Omicron period in South Korea. This finding may reflect the difference in risk of exposure between the population, such as young adults and healthcare professionals, with a persistently higher risk of exposure compared to the general population. In South Korea, the increase of SARS‐CoV‐2 cases during the first half of 2022 was largely driven by children and adolescents with limited vaccine coverage, suggesting a possible role of vaccine‐induced immunity in preventing SARS‐CoV‐2 reinfections. Higher rates of reinfection among children (470 per 100 000, compared to 240–280 per 100 000 in adults) and unvaccinated persons (530–640 per 100 000, compared to 210‐400 per 100 000 in fully vaccinated persons) support such hypothesis. This higher vaccination coverage could lead to a lesser chance of reinfections in the community.

The result of this study should be interpreted with caution given the lack of genomic confirmation in each case. The difference in health‐seeking behavior may have resulted in an overestimation of the association between reinfection and vaccination status. Moreover, the likelihood of false positive due to the re‐positive test for SARS‐CoV‐2, irrespective of reinfection may have occurred. A previous study has shown that re‐positive tests for SARS‐CoV‐2 by RT‐PCR in recovered COVID‐19 patients were seen in 2.4%–69.2% of cases. The duration of SARS‐CoV‐2 positive result of more than 3 weeks was common in mild or asymptomatic patients. Lastly, other social (residence, educational level) or medical (comorbidities, medication) conditions may have affected the result, which was not accounted in the current analysis. Despite these limitations, our finding suggests that the majority of possible reinfections occurred following the emergence of new variants. The difference in population risk of exposure to the new circulating variant, according to the vaccination status, provides a clue to public health preparedness for the next possible SARS‐CoV‐2 variant of concern. We recommend expanding vaccination to eligible persons, including those with previous SARS‐CoV‐2 infection, to minimize the community outbreak of the new SARS‐CoV‐2 variant.

AUTHOR CONTRIBUTIONS

Eun Jung Jang and Young June Choe conceived and designed the study. Go‐Woon Yun gathered, processed, and sorted the data. Seongjin Wang did the record linkage. Eun Jung Jang, U Jin Cho, and Young June Choe analyzed the data. Eun Jung Jang and Young June Choe wrote the first draft of the manuscript followed by an iterative revision with all other authors. All authors substantially contributed to the discussion of content and reviewed and edited the manuscript before submission. All authors were involved in the decision to submit and agreed to publish the paper.

CONFLICT OF INTEREST

The authors declare no conflict of interest.