Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection by Type and Frequency of Vaccine: A Community-Based Case-Control Study

Hyerin Gim; Haesook Seo; Byung Chul Chun

doi:10.3346/jkms.2024.39.e174

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Gim, Seo, and Chun: Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection by Type and Frequency of Vaccine: A Community-Based Case-Control Study

Original Article

Infectious Diseases

Journal of Korean Medical Science 2024; 39(21): e174.

Published online: 20 May 2024

DOI: https://doi.org/10.3346/jkms.2024.39.e174

Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection by Type and Frequency of Vaccine: A Community-Based Case-Control Study

Hyerin Gim¹

, Haesook Seo¹

, Byung Chul Chun^2,³

¹Infectious Disease Research Center, Citizens’ Health Bureau, Seoul Metropolitan Government, Seoul, Korea.

²Department of Epidemiology & Health Informatics, Graduate School of Public Health, Korea University, Seoul, Korea.

³Department of Preventive Medicine, Korea University College of Medicine, Seoul, Korea.

Address for Correspondence: Byung Chul Chun, MD, MPH, PhD. Department of Epidemiology & Health Informatics, Graduate School of Public Health and Department of Preventive Medicine, College of Medicine, Korea University, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Korea. chun@korea.ac.kr

Received 4 December 2023 Accepted 7 May 2024

The Korean Academy of Medical Sciences

https://creativecommons.org/licenses/by-nc/4.0/

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Although guidelines recommend vaccination for individuals who have recovered from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to prevent reinfection, comprehensive evaluation studies are limited. We aimed to evaluate vaccine effectiveness against SARS-CoV-2 reinfection according to the primary vaccination status, booster vaccination status, and vaccination methods used.

Methods

This population-based case-control study enrolled all SARS-CoV-2-infected patients in Seoul between January 2020 and February 2022. Individuals were categorized into case (reinfection) and control (no reinfection) groups. Data were analyzed using conditional logistic regression after adjusting for underlying comorbidities using multiple regression.

Results

The case group included 7,678 participants (average age: 32.26 years). In all vaccinated individuals, patients who received the first and second booster doses showed reduced reinfection rates compared with individuals who received basic vaccination (odds ratio [OR] = 0.605, P < 0.001 and OR = 0.002, P < 0.001). Patients who received BNT162b2 or mRNA-1273, NVX-CoV2373 and heterologous vaccination showed reduced reinfection rates compared with unvaccinated individuals (OR = 0.546, P < 0.001; OR = 0.356, P < 0.001; and OR = 0.472, P < 0.001). However, the ChAdOx1-S or Ad26.COV2.S vaccination group showed a higher reinfection rate than the BNT162b2 or mRNA-1273 vaccination group (OR = 4.419, P < 0.001).

Conclusion

In SARS-CoV-2-infected individuals, completion of the basic vaccination series showed significant protection against reinfection compared with no vaccination. If the first or second booster vaccination was received, the protective effect against reinfection was higher than that of basic vaccination; when vaccinated with BNT162b2 or mRNA-1273 only or heterologous vaccination, the protective effect was higher than that of ChAdOx1-S or Ad26.COV2.S vaccination only.

Graphical Abstract

Keywords: Coronavirus Disease 2019, Reinfection, Severe Acute Respiratory Syndrome Coronavirus 2, Vaccine Effectiveness

INTRODUCTION

The World Health Organization announced the lifting of the designation of Public Health Emergency of International Concern for coronavirus disease 2019 (COVID-19) approximately 3 years and 4 months after its declaration on January 30, 2020. Despite the ongoing global risk posed by COVID-19, the decision to transition to a long-term management phase considers the decline in cases, the resilience of healthcare systems, and attainment of a high level of population immunity.

The existing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine regimens are effective against various variants (alpha,1 delta,2 and omicron3). Additionally, bivalent SARS-CoV-2 mRNA vaccines (BNT162b2 or mRNA-1273) significantly contribute to the prevention of symptomatic SARS-CoV-2 infection.4 Previous clinical studies have shown that the protective efficacy against the omicron variant increased by 31% after the third vaccine dose and by 75% after the fourth vaccine dose.5 Moreover, vaccination after infection resulted in increased protection compared with no vaccination, with a 96% protection probability after receiving two doses of mRNA vaccine.6 Multiple guidelines also recommend vaccination for individuals who have recovered from infection to prevent reinfection.7 8 However, despite the effectiveness of these vaccines, breakthrough infections and reinfections continue to occur.9

SARS-CoV-2 vaccination, using multiple types of vaccines and administering multiple booster doses within a short timeframe, represents a novel approach to preventive immunization in many countries. This approach significantly departs from conventional vaccination practices, including the possibility of cross-vaccination with different vaccine types in certain patient groups. Moreover, mRNA and other platforms have been developed and employed for the first time, emphasizing the need for comparisons and evaluations of vaccines developed on these distinct platforms and for assessment of their cross-reactivity or effectiveness. Furthermore, the administration of up to two booster doses within a short period is unprecedented, and the meticulous evaluation of patients who have received these doses is required. In addition, studies investigating the incidence of reinfection and post-COVID-19 complications are limited, emphasizing the need for further investigations in the future.10

This study aimed to evaluate the effectiveness of SARS-CoV-2 vaccines in preventing reinfection by enrolling individuals of all ages who experienced reinfection in Seoul, South Korea, from January 2020 to February 2022, in a community-based study. The effectiveness of five different vaccine types, as well as cases involving cross-vaccinations, and the impact of vaccination frequency (both primary and booster doses), were evaluated.

METHODS

Study design

This community-based case-control study used COVID-19 case data collected internally by the local government authority of Seoul Metropolitan City. All data used in the study, including the infected case and vaccine data, were collected from secondary sources that were already generated by hospitals, public health centers, and screening clinics.

Study participants

This study included all SARS-CoV-2 infected patients of all ages living in Seoul from January 2020 to February 24, 2022. In this study, the group of patients experiencing reinfection was defined as the case group. The patient group comprised individuals who had two instances of SARS-CoV-2 infection based on the reverse transcription-polymerase chain reaction (RT-PCR) test using nasopharyngeal swabs conducted at all testing centers in Seoul until February 24, 2022. Individuals with missing information such as sex, date of birth, or vaccine information were excluded. Reinfection was defined as a second positive SARS-CoV-2 RT-PCR test result at least 90 days after the initial occurrence of infection; this delineation has garnered acceptance among numerous scientists and organizations, prominently including the Centers for Disease Control and Prevention (CDC).11 12 13 The control group comprised individuals who did not experience reinfection within 90 days after the initial positive result among those who tested positive for SARS-CoV-2 on RT-PCR tests performed in all centers in Seoul. During the selection of the control group, the case group was first divided into age groups: 0–9, 10–19, 20–29, 30–39, 40–49, 50–59, 60–69, 70–79, and > 80 years. Subsequently, the control group was then randomly assigned within each age group, based on a 1:2 ratio relative to the corresponding age groups in the case group. This method helped to mitigate age-group bias between the control and case groups (Fig. 1). To reduce bias resulting from differences in observation periods between the case and control groups, the study was conducted with matched observation periods for both groups.

Fig. 1

Exclusion and inclusion criteria for study participant selection.

RT-PCR = reverse transcription-polymerase chain reaction, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

Study variables

In South Korea, SARS-CoV-2 RT-PCR testing was available free of charge to the entire population from January 2020 to January 2022. If the RT-PCR of tested patients yielded a positive result, the complete data of these patients were immediately uploaded to the Disease Control and Prevention Integrated System (DCPIS) of the Korea Disease Control and Prevention Agency (KDCA). The collected data were reported as single instances; reinfection was determined when the same individual developed infections on two or more instances, with an interval of at least 90 days between confirmations, among the reported patients.

The vaccine data used in this study were obtained from the DCPIS, a real-time national vaccination record system that ensures comprehensive data collection without missing any vaccine recipients. The vaccines included in this study were those recognized for their efficacy14 15 16 17 and currently administered in South Korea—mRNA vaccine (BNT162b2 [Tozinameran, Pfizer-BioNTech] or mRNA-1273 [Elasomeran, Moderna]), Vector vaccine (Ad26.COV2.S [Jcovden, previously COVID-19 Vaccine Janssen] or ChAdOx1-S [recombinant] COVID-19 vaccine [AstraZeneca, ChAdOx1-S]), and NVX-CoV2373 (Nuvaxovid, Nova vaccine), which were approved for use by the KDCA on February 22, 2021. The vaccination data obtained from February 26, 2021 (the period of vaccination initiation in South Korea) to February 24, 2022 were used in this study.

Basic vaccination involved the administration of two doses of a BNT162b2, mRNA-1273, ChAdOx1-S, or NVX-CoV2373 vaccine, or a single dose of the Ad26.COV2.S vaccine.18 Booster vaccination involved the administration of one or more additional vaccine doses after the completion of the basic vaccination regimen, and were categorized as the first booster and second booster vaccination (Supplementary Table 1). Unvaccinated individuals refer to those who did not receive the SARS-CoV-2 vaccine or received only a single dose. mRNA vaccination means received vaccine only of mRNA (BNT162b2 [Tozinameran, Pfizer-BioNTech] or mRNA-1273 [Elasomeran, Moderna]) vaccines before February 24, 2022. Vector vaccination means received vaccine only of Ad26.COV2.S (Jcovden) or ChAdOx1-S [recombinant] COVID-19 (AstraZeneca, ChAdOx1-S) vaccines before February 24, 2022. Nova vaccination means received vaccine only of NVX-CoV2373 (Nuvaxovid, Novavax) vaccines before February 24, 2022. Heterologous vaccinations means received vaccine only of mRNA (BNT162b2 [Tozinameran, Pfizer-BioNTech] or mRNA-1273 [Elasomeran, Moderna]) or Ad26.COV2.S (Jcovden) or ChAdOx1-S [recombinant] COVID-19 (AstraZeneca, ChAdOx1-S) or NVX-CoV2373 (Nuvaxovid, Novavax) vaccines before February 24, 2022.

The collected data on infected cases and vaccine administration status were integrated into a single dataset for analysis, and the analysis of the vaccine effectiveness (VE) was conducted according to the timing of vaccination by dividing the patients into two groups based on whether the vaccination occurred before or after the SARS-CoV-2 infection (Supplementary Table 2). To exclude immortal time bias, if vaccination occurred before the infection and the interval between the vaccination date and the infection date was at least 14 days have passed, the vaccine was considered eligible. Therefore, data of patients whose interval between vaccination and infection was 13 days or less were excluded from the analysis. Moreover, we conducted by aligning the observation timeline of unvaccinated and vaccinated individuals in the case and control groups.

Based on previous research findings, which provide strong epidemiological evidence, underlying conditions such as cardiovascular, liver, kidney, pulmonary, cerebrovascular, and autoimmune diseases, hypertension, diabetes, chronic neurological disorders, and immunodeficiency disorders19 20 21 22 can serve as significant confounding factors that may impact the occurrence, severity, and prognosis of COVID-19 as well as the mortality rates (Supplementary Table 3).

Statistical analyses

Descriptive statistics were used to characterize the patients. Logistic regression analysis was performed for univariate analyses to estimate the association between vaccine-type, heterologous vaccination, the impact of vaccination frequency (primary vaccination and booster vaccination [first and second doses]), timing of vaccination, and reinfection. A multivariate logistic regression model with underlying morbidity covariates was used to estimate the association between all covariates and reinfection. A P value of < 0.05 was considered significant.

The infection status and vaccine data were integrated separately using the patient’s name, date of birth, residential district, and sex as key values. The day when the RT-PCR test was conducted was set as the reference point for the infection date; the period from the date of initial infection to the date of reinfection and the period until the date of vaccination were calculated using the date of initial infection (day 1).

The association between vaccine-type heterologous vaccination, impact of vaccination frequency, timing of vaccination, and reinfection was estimated using a multivariate logistic regression model after adjusting for age. Further, as underlying comorbidities can serve as confounding factors for SARS-CoV-2 infection and severity,23 multivariate logistic regression analyses of the underlying morbidities were performed according to the study design.

All covariates were tested for interactions with the reinfection. The variables that met the testing criteria and were significantly associated with the outcome served as the inputs for multivariate regression analysis. VE was calculated as 1 minus the matched odds ratio (OR), which was estimated using logistic regression.

The SPSS software version 24 (IBM, Armonk, NY, USA) was used to perform all statistical analyses.

Ethics statement

Ethical approval for the data collection and research was obtained from the Institutional Review Board of the Ministry of Health and Welfare of Korea (approval No.: P01-202301-01-001). As this research was a retrospective study that used secondary data, the need for prior consent was waived.

RESULTS

During the study period, 23,034 patients met the eligibility criteria. Of these patients, 7,678 were reinfected with SARS-CoV-2 and 15,356 were infected with SARS-CoV-2 once.

The patients’ mean age was 32.28 years, and 47.5% were men. No significant differences were observed in the age, sex, or body mass index between the case and control groups. The average number of underlying morbidities per patient (1.46) was significantly higher in the case group than in the control group. In particular, the prevalence of chronic pulmonary diseases was significantly higher in the patient group (4.19%) than in the control group (0.74%). The most common underlying morbidities in both groups were hypertension and diabetes mellitus. The vaccination rate was higher in the control group (72.4%) than in the patient group (55.9%). Additionally, the booster vaccination rate was significantly higher in the control group (56.1%) than in the patient group (43.1%). Compared with the case group, the control group had a significantly higher proportion of mRNA vaccine recipients (71.1% and 76.8%, respectively) (Table 1). During the follow-up period, an increasing trend was observed in the number of infections and reinfections, which exhibited a continuous increase in incidence from July 2021 to February 2022 (Supplementary Fig. 1).

Table 1

Demographics, BMI, and underlying comorbidities among confirmed SARS-CoV-2 reinfection cases reported to the system (July 2021 to February 2022)

Characteristics			Total	Cases	Controls	P value
Total			23,034 (100.0)	7,678 (100.0)	15,356 (100.0)
Age, yr						1.000
	Mean ± SD		32.28 ± 21.14	32.26 ± 21.12	32.28 ± 21.15
		0–9	3,561 (15.5)	1,187 (15.5)	2,374 (15.5)
		10–19	4,404 (19.1)	1,468 (19.1)	2,936 (19.1)
		20–29	3,687 (16.0)	1,229 (16.0)	2,458 (16.0)
		30–39	3,459 (15.0)	1,153 (15.0)	2,306 (15.0)
		40–49	2,856 (12.4)	952 (12.4)	1,904 (12.4)
		50–59	1,836 (8.0)	612 (8.0)	1,224 (8.0)
		60–69	1,968 (8.5)	656 (8.5)	1,312 (8.5)
		70–79	828 (3.6)	276 (3.6)	552 (3.6)
		> 80	435 (1.9)	145 (1.9)	290 (1.9)
Sex						0.240
	Female		12,093 (52.5)	4,073 (53.0)	8,020 (52.2)
	Male		10,941 (47.5)	3,605 (47.0)	7,336 (47.8)
BMI, kg/m²
	Total		12,378 (53.7)	4,442 (57.9)	7,936 (51.7)
	Mean ± SD		22.31 ± 4.27	22.32 ± 4.32	22.30 ± 4.28	0.332
		< 18.5	2,187 ± 9.49	803 ± 10.46	1,384 ± 9.01
		18.5–22.9	5,084 ± 22.07	1,786 ± 23.26	3,298 ± 21.48
		23.0–24.9	2,202 ± 9.56	793 ± 10.33	1,409 ± 9.18
		25.0–29.9	2,374 ± 10.31	871 ± 11.34	1,503 ± 9.79
		30.0–34.9	429 ± 1.86	145 ± 1.89	284 ± 1.85
		> 35.0	102 ± 0.44	44 ± 0.57	58 ± 0.38
Underlying morbidities^a
	Total		2,705 (11.7)	1,389 (18.1)	1,316 (8.6)
	Mean ± SD		1.42 ± 0.72	1.46 ± 0.76	1.38 ± 0.67	< 0.001
		Hypertension	1,504 ± 6.53	697 ± 9.08	807 ± 5.26	< 0.001
		Diabetes mellitus	741 ± 3.22	334 ± 4.35	407 ± 2.65	< 0.001
		Cancer	243 ± 1.05	115 ± 1.50	128 ± 0.83	< 0.001
		Cardiovascular diseases	308 ± 1.34	163 ± 2.12	145 ± 0.94	< 0.001
		Liver diseases	64 ± 0.28	47 ± 0.61	17 ± 0.11	< 0.001
		Chronic kidney diseases	161 ± 0.70	93 ± 1.21	68 ± 0.44	< 0.001
		Chronic pulmonary diseases	436 ± 1.89	322 ± 4.19	114 ± 0.74	< 0.001
		Cerebrovascular accident	186 ± 0.81	110 ± 1.43	76 ± 0.49	< 0.001
		Autoimmune diseases	51 ± 0.22	37 ± 0.48	14 ± 0.09	< 0.001
		Chronic neurological diseases	134 ± 0.58	97 ± 1.26	37 ± 0.24	< 0.001
		Other (immunocompromised)	11 ± 0.05	9 ± 0.12	2 ± 0.01	0.001
Vaccination^b
	No		7,620 (33.1)	3,383 (44.1)	4,237 (27.6)	< 0.001
	Yes^c		1,414 (66.9)	4,295 (55.9)	11,119 (72.4)
	Times of vaccination					< 0.001
		Basic	7,326 (47.5)	2,442 (56.9)	4,884 (43.9)
		First booster	7,230 (46.9)	1,851 (43.1)	5,379 (48.4)
		Second booster	858 (5.6)	2 (0.0)	856 (7.7)
	Type of vaccination until infection or reinfection					< 0.001
		mRNA only	11,596 (75.2)	3,055 (71.1)	8,541 (76.8)
		Vector only	421 (2.7)	276 (6.4)	145 (1.3)
		Nova only	10 (0.1)	1 (0.0)	9 (0.1)
		Heterologous vaccination	3,387 (22.0)	963 (22.4)	2,424 (21.8)

Data are number (%) not otherwise specified. Participants had been resident in Seoul since February 1, 2020.

BMI = body mass index, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2, SD = standard deviation.

^aComorbidities reported at the time of SARS-CoV-2 infection.

^bVaccinations received by February 24, 2022; mRNA vaccines were either BNT162b2 (Tozinameran, Pfizer-BioNTech) or mRNA-1273 (Elasomeran, Moderna); Vector vaccines were Ad26.COV2.S (Jcovden, previously COVID-19 Vaccine Janssen) and ChAdOx1-S [recombinant] COVID-19 vaccine (AstraZeneca, ChAdOx1-S); Nova vaccines were NVX-CoV2373 (Nuvaxovid, Novavax).

^cIncomplete primary vaccination series or unvaccinated.

The OR of patients suspected of having SARS-CoV-2 reinfection was higher compared with that of patients with primary infection according to vaccination status, type of vaccine, and vaccination time. In all patients, the OR of vaccinated individuals was 0.605 (95% confidence interval [CI], 0.565–0.647; P < 0.001) (Table 2), showing a reduced reinfection rate compared with unvaccinated individuals (OR < 1). In all vaccinated individuals, the ORs of patients who received the first and second booster doses were 0.605 (95% CI, 0.561–0.653; P < 0.001) and 0.002 (95% CI, 0.001–0.009; P < 0.001), showing a reduced reinfection rate compared with those of individuals who received basic vaccination (OR < 1) (Table 2, Supplementary Tables 4, 5, 6). In all patients, the ORs of patients who received mRNA, Nova vaccination only, and heterologous vaccination were 0.546 (95% CI, 0.513–0.581; P < 0.001), 0.356 (95% CI, 0.131–0.967; P = 0.043), and 0.472 (95% CI, 0.430–0.518; P < 0.001), showing reduced reinfection rates compared with unvaccinated individuals (OR < 1). However, the OR was significantly increased among those who received vector vaccination only (OR, 2.088; 95% CI, 1.694–2.573; P < 0.001). In all vaccinated individuals, the OR of the vector vaccination only was 4.419 (95% CI, 3.578–5.458; P < 0.001), showing an increased reinfection rate compared with that of the mRNA vaccination only (OR < 1) (Table 3, Supplementary Tables 7 and 8).

Table 2

Vaccine protection against SARS-CoV-2 reinfection in Seoul, by vaccination timing (unvaccinated, basic, first booster, or second booster)

Variables		Cases	Controls	Unadjusted OR	Adjusted OR^a
All study participants
	Unvaccinated	3,383 (44.1)	4,237 (27.6)	1 [Reference]	1 [Reference]
	Basic^b	2,442 (31.8)	4,884 (31.8)	0.626 (0.586–0.669)	0.605 (0.565–0.647)
	First booster^c	1,851 (24.1)	5,379 (35.0)	0.431 (0.402–0.462)	0.365 (0.339–0.393)
	Second booster^d	2 (0.0)	856 (5.6)	0.003 (0.001–0.012)	0.001 (0.000–0.005)
Vaccination participants alone
	Basic^b	2,442 (31.8)	4,884 (31.8)	1 [Reference]	1 [Reference]
	First booster^c	1,851 (24.1)	5,379 (35.0)	0.688 (0.641–0.739)	0.605 (0.561–0.653)
	Second booster^d	2 (0.0)	856 (5.6)	0.005 (0.001–0.019)	0.002 (0.001–0.009)

Data are number (%) or OR(95% confidence interval). All participants were infected with SARS-CoV-2. The outcome period was between January 1, 2020 and February 24, 2022. Cases were reinfected with SARS-CoV-2 during the outcome period. Controls were only infected once with SARS-CoV-2 during the outcome period.

SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2, OR = odds ratio.

^aAdjusted for underlying diseases (hypertension, diabetes mellitus, cancer, cardiovascular disease, liver diseases, chronic kidney diseases, chronic lung diseases, cerebrovascular accident, autoimmune disease, chronic neurological disease, and other immunocompromising diseases).

^bCompleted primary vaccination series before the start of the outcome period.

^cReceived first booster vaccine of mRNA (BNT162b2 [Tozinameran, Pfizer-BioNTech] or mRNA-1273 [Elasomeran, Moderna]) or Ad26.COV2.S (Jcovden, previously COVID-19 Vaccine Janssen) or ChAdOx1-S [recombinant] COVID-19 (AstraZeneca, ChAdOx1-S) or NVX-CoV2373 (Nuvaxovid, Novavax) vaccines before February 24, 2022.

^dReceived second booster vaccine of mRNA (BNT162b2 [Tozinameran, Pfizer-BioNTech] or mRNA-1273 [Elasomeran, Moderna]) or Ad26.COV2.S (Jcovden, previously COVID-19 Vaccine Janssen) or ChAdOx1-S [recombinant] COVID-19 (AstraZeneca, ChAdOx1-S) or NVX-CoV2373 (Nuvaxovid, Novavax) vaccines before February 24, 2022.

Table 3

Vaccine protection against SARS-CoV-2 reinfection in Seoul, by vaccine type (unvaccinated, mRNA, vector, Nova, or Heterologous vaccination) before the study period

Variables		Cases	Controls	Unadjusted OR	Adjusted OR^a
All study participants
	Unvaccinated	3,383 (44.1)	4,237 (27.6)	1 [Reference]	1 [Reference]
	mRNA only^b	3,055 (39.8)	8,541 (55.6)	0.562 (0.529–0.598)	0.546 (0.513–0.581)
	Vector only^c	276 (3.6)	145 (0.9)	2.610 (2.132–3.196)	2.088 (1.694–2.573)
	Nova only^d	1 (0.0)	9 (0.1)	0.387 (0.143–1.043)	0.356 (0.131–0.967)
	Heterologous vaccination^e	963 (12.5)	2,424 (15.8)	0.553 (0.506–0.604)	0.472 (0.430–0.518)
Vaccination participants alone
	mRNA only^b	3,055 (71.1)	8,541 (76.8)	1 [Reference]	1 [Reference]
	Vector only^c	276 (6.4)	145 (1.3)	5.322 (4.334–6.534)	4.419 (3.578–5.458)
	Nova only^d	1 (0.0)	9 (0.1)	0.311 (0.039–2.453)	0.336 (0.043–2.658)
	Heterologous vaccination^e	963 (22.4)	2,424 (21.8)	1.111 (1.020–1.210)	0.987 (0.903–1.079)

Data are number (%) or OR (95% confidence interval). All participants were infected with SARS-CoV-2. The outcome period was between January 1, 2020 and February 24, 2022. Cases were reinfected with SARS-CoV-2 during the outcome period. Controls were only infected once with SARS-CoV-2 during the outcome period.

SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2, OR = odds ratio.

^bReceived vaccine only of mRNA (BNT162b2 [Tozinameran, Pfizer-BioNTech] or mRNA-1273 [Elasomeran, Moderna]) vaccines before February 24, 2022.

^cReceived vaccine only of Ad26.COV2.S (Jcovden, previously COVID-19 Vaccine Janssen) or ChAdOx1-S [recombinant] COVID-19 (AstraZeneca, ChAdOx1-S) vaccines before February 24, 2022.

^dReceived vaccine only of NVX-CoV2373 (Nuvaxovid, Novavax) vaccines before February 24, 2022.

^eReceived vaccine only of mRNA (BNT162b2 [Tozinameran, Pfizer-BioNTech] or mRNA-1273 [Elasomeran, Moderna]) or Ad26.COV2.S (Jcovden, previously COVID-19 Vaccine Janssen) or ChAdOx1-S [recombinant] COVID-19 (AstraZeneca, ChAdOx1-S) or NVX-CoV2373 (Nuvaxovid, Novavax) vaccines before February 24, 2022.

DISCUSSION

This community-based cohort study that considered all individuals of all ages who experienced reinfection in Seoul provided evidence of the appropriate vaccination methods for protection against SARS-CoV-2 reinfection after the initial infection from February 2020 to February 2022. Substantial levels of protection against SARS-CoV-2 reinfection were achieved after receiving booster vaccinations and mRNA or heterologous vaccination.

The preventive efficacy against reinfection increased with the number of vaccine doses administered. Compared to unvaccinated individuals, vaccination protected against SARS-CoV-2 reinfection in 39.5% of individuals who received the basic vaccination, 63.5% after receiving the first booster vaccination, and 99.9% after receiving the second booster vaccination. These findings were consistent with those of the vaccinated group. Despite the emergence of highly transmissible variants as the dominant circulating strains, an increase in the number of vaccine doses has provided enhanced protection against reinfection. Therefore, the frequency of vaccine administration plays a crucial role in reducing the reinfection rates. This result aligns with that of a previous Israeli study, which reported that BNT162b2 vaccination showed a lower incidence of reinfection among vaccinated individuals (2.46 cases per 100,000 person-days) than among unvaccinated individuals (10.21 cases per 100,000 person-days).24

The effectiveness of booster vaccination in preventing COVID-19 is consistent with the findings of a previous study conducted in Canada, which demonstrated an increased VE as the number of vaccine doses administered increased during both pre-omicron and post-omicron periods.25 In a South Korean study focusing on mRNA vaccines, the incidence rates of COVID-19 among individuals aged 60 years and above were 8.36 cases per 100,000 population after receiving the primary vaccination and 2.70 cases per 100,000 population after receiving booster vaccinations.26 In Israel, a study showed that the second booster dose provides additional protection against SARS-CoV-2 infection compared to the first booster doses.27 However, previous research indicates that while booster vaccination reinstates VE to the level observed immediately after the basic vaccination, it diminishes thereafter.27 28 Therefore, the significance of our findings should be taken into account regarding the allocation of vaccine resources, especially in the context of deliberating booster vaccine doses for high-risk populations.

Vaccination may offer protection against SARS-CoV-2 reinfection, with no significant difference observed between heterologous vaccination and mRNA vaccination. However, both mRNA and heterologous vaccinations demonstrated over four times greater effectiveness than the vector vaccines alone. A previous study conducted in the United States, which examined the protective effects of different vaccine types against infection, indicated that mRNA vaccines exhibited higher efficacy compared to vector vaccines.29 In a clinical study comparing the effects of different vaccine types and heterologous vaccination, heterologous vaccination with mRNA and vector vaccines yielded excellent outcomes. Additionally, the mRNA vaccines alone demonstrated higher protective efficacy than vector vaccines alone.30 31 Concerning booster vaccination, mRNA vaccines continued to exhibit superior efficacy compared to the vector vaccines.32

Our study has several strengths. First, the results were based on the DCPIS of the KDCA, which included detailed population statistics, test results from different laboratory facilities, and complete data on the dates and results of RT-quantitative PCR (RT-qPCR) testing. Local public health centers in each region updated the information daily in the national data network. Second, this large-scale cohort study, conducted on the entire population of Seoul, allowed for long-term follow-up analysis. Third, SARS-CoV-2 vaccination in South Korea was only administered to individuals who preferred to receive it, with vaccination priority initially targeting the elderly population and gradually expanding to the younger age groups. To mitigate the sampling bias resulting from different vaccination timings according to age, the patient group included 7,678 individuals with confirmed reinfection identified through RT-PCR testing, and the control group included 15,356 individuals randomly selected and matched with the case group with the same age distribution as that of the patient group in a 1:2 ratio. Fourth, both case and control groups were not included if the infection was confirmed within 14 days of vaccination to exclude immortal time bias. Moreover, among unvaccinated individuals in both groups, we excluded those who had been reinfected before the median vaccination date of all vaccinated individuals (start point of observation for vaccinated individuals). That is, we conducted the study by aligning the observation points of unvaccinated individuals in the case and control groups with the observation points of vaccinated individuals. Therefore, immortal time bias according to the observation period did not occur in this study. Fifth, the timing of vaccination (Basic, 1st booster, 2nd booster vaccination) for the patient group and the control group was similar, thereby minimizing any potential biases. Sixth, we investigated the effectiveness of all five vaccines administered in Seoul. Assessing the protective effects of different vaccine types and doses across all age groups is crucial for public health decision-making regarding vaccine mandates and recommendations for preventing reinfection.

Our study has some limitations. Despite our attempts to address the individual-level confounding factors, such as age and comorbidities, there may still be unobserved or unmeasured sources of bias that were not appropriately measured or adjusted for. Additionally, bias could have been introduced by changes in exposure to SARS-CoV-2 during the study period. To minimize this potential bias, only those who developed infection until February 24, 2022, were included in the study, as the omicron variant with a faster transmission rate emerged after that date. Furthermore, the study proceeded by aligning the observation periods of the case and control groups; however, caution is advised in interpreting the study results due to the potentially insufficient observation time, especially after the second booster vaccination. Another limitation of this study is that reinfection was confirmed based on the positive results from RT-qPCR analysis, which may have missed those individuals who were reinfected but had mild symptoms or chose to avoid RT-qPCR testing. Individuals who received the vaccination may have a higher likelihood of developing asymptomatic or mild infections, leading to a lower probability of being tested. Therefore, a substantial number of infection data may have been missed, which could have significantly distorted the reinfection rates in the vaccinated group, leading to an overestimation of the VE.

Nevertheless, our data were comprehensively collected from SARS-CoV-2 infection records in Seoul without omissions. Furthermore, we meticulously controlled for various biases, allowing us to observe the effectiveness of SARS-CoV-2 vaccination in preventing reinfection from multiple perspectives. Therefore, the findings of this study can be considered valuable.

In conclusion, this study demonstrates that vaccination reduces the risk of SARS-CoV-2 reinfection, with VE increasing as the number of vaccine doses administered increased. These findings indirectly suggest that as SARS-CoV-2 becomes endemic, annual vaccination can enhance the prevention of reinfection. To establish a foundation for annual vaccination programs, further research is necessary at the community level, considering the potential side effects of the vaccines and their impact on mortality. Moreover, mRNA and heterologous vaccinations demonstrated significantly higher effectiveness than the vector-based vaccines. These findings provide scientific evidence for the establishment of effective SARS-CoV-2 vaccination policies aimed at preventing reinfection during the endemic phase of COVID-19, thereby contributing to improved public health.

ACKNOWLEDGMENTS

We would like to extend our gratitude to the Big Data Team of the Korea Disease Control and Prevention Agency for their valuable contributions.

Notes

Disclosure: The authors have no potential conflicts of interest to disclose.

Author Contributions:

Conceptualization: Gim H, Chun BC.
Data curation: Gim H.
Formal analysis: Gim H.
Funding acquisition: Seo H.
Investigation: Gim H, Chun BC.
Methodology: Gim H, Chun BC.
Project administration: Gim H, Chun BC.
Resources: Gim H.
Software: Gim H.
Supervision: Seo H, Chun BC.
Validation: Gim H.
Visualization: Gim H.
Writing - original draft: Gim H.
Writing - review & editing: Gim H, Chun BC.

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SUPPLEMENTARY MATERIALS

Supplementary Table 1

Number of vaccinated research patients for the five types of vaccines implemented in South Korea

jkms-39-e174-s001.doc

Supplementary Table 2

Distribution of cases (reinfection) and controls (infection once) by timing of vaccination completion

jkms-39-e174-s002.doc

Supplementary Table 3

Selection of significant underlying morbidities potentially impacting SARS-CoV-2 infection and severity

jkms-39-e174-s003.doc

Supplementary Table 4

Vaccine protection against SARS-CoV-2 reinfection in Seoul, by vaccination status and underlying morbidities

jkms-39-e174-s004.doc

Supplementary Table 5

Vaccine protection against SARS-CoV-2 reinfection in Seoul, by vaccination timing (unvaccinated, basic, or booster) and underlying morbidities

jkms-39-e174-s005.doc

Supplementary Table 6

Vaccine protection against SARS-CoV-2 reinfection in Seoul, by vaccination timing (unvaccinated, basic, first booster, or second booster) and underlying morbidities

jkms-39-e174-s006.doc

Supplementary Table 7

Vaccine protection against SARS-CoV-2 reinfection in Seoul, by vaccine type (unvaccinated, mRNA, vector, Nova, or Heterologous vaccination) before the study period and underlying morbidities

jkms-39-e174-s007.doc

Supplementary Table 8

Vaccine protection against SARS-CoV-2 reinfection in Seoul, by vaccine type (unvaccinated, mRNA, vector, or Heterologous vaccination) before the study period and underlying morbidities

jkms-39-e174-s008.doc

Supplementary Fig. 1

Cumulative number of SARS-CoV-2 reinfection cases reported to the system by date of report: July 2021 to February 2022.

jkms-39-e174-s009.doc

TOOLS

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