Реальное воздействие NVX-CoV2373 COVID-19 вакцина для иммунокомпромиссных людей в Южной Корее.

Introduction

Emerging in 2019, SARS-CoV-2 triggered the global COVID-19 pandemic. Despite the announcement of the end of the pandemic in May 2023, the ongoing evolution of new strains continues to pose a substantial global health threat [ 1 ]. The evolution of immune-evasive variants has underscored the necessity for ongoing vaccine development and adaptation [ 2 , 3 ]. While various vaccines have been authorized/approved for use, their impact in specific populations, particularly individuals who are immunocompromised (IIC), remains a critical area of investigation based on the increased susceptibility to infection and progression to severe/critical disease among IIC [ 4 ].

IIC comprise 2% to 3% of the overall population and are a heterogeneous group of individuals with genetic or acquired conditions that disrupt normal immune function and/or are taking essential immune-modifying therapies after certain procedures (e.g., organ transplants) or to control disease [ 5 , 6 ]. Higher rates of COVID-19–related hospitalizations in IIC [ 4 , 7 ] defined the group as an at-risk population, supporting their eligibility in South Korea to receive biannual vaccinations (versus a single seasonal dose) for additional protection against infection/disease [ 8 ].

IIC are often excluded from or vastly underrepresented in clinical trials of vaccines, and meta-analyses and systematic reviews of COVID-19 vaccine clinical trials have mostly focused on mRNA-based COVID-19 vaccines [ 9 – 12 ]. Because of altered immune responses, IIC may not elicit as robust responses to a vaccine as non-immunocompromised (non-IC) individuals, having presented with lower seroconversion rates [ 13 ] and vaccine impact [ 14 ]. Previous studies of mRNA COVID-19 vaccines in IIC have found lower vaccine effectiveness in these groups, compared with the general population [ 15 ]. For that reason, understanding the real-world impact of different vaccines in IIC is paramount for optimizing vaccination strategies and protecting this high-risk group.

The Novavax COVID-19 vaccine is a nanoparticle vaccine expressing recombinant SARS-CoV-2 spike (rS) protein with Matrix-M ® adjuvant. A formulation targeting ancestral SARS-CoV-2 (NVX-CoV2373) was authorized for use in South Korea in 2022 and has since been amended for use of updated formulations targeting relevant variant strains (NVX-CoV2601 [XBB.1.5]; NVX-CoV2705 [JN.1]) [ 16 ]. In the general population, NVX-CoV2373 demonstrated high efficacy in clinical trials, providing a benchmark for its expected performance in IIC [ 11 , 17 ]. Notably, little immunogenicity data for NVX-CoV2373 in immunocompromised individuals exists [ 18 ], underscoring the importance of this real-world study investigating vaccine impact.

We aimed to assess whether NVX-CoV2373 reduced the risk of SARS-CoV-2 infection and severe disease in IIC, compared to non-IC individuals. By utilizing population-based data from the period when Omicron variants (e.g., BA.1/1.1, BA.2/2.3, and BA.5/5.2) [ 19 ] predominated, we seek to provide valuable real-world insights into the vaccine’s performance in relation to immunocompromised status in South Korea. This real-world study compares SARS-CoV-2 infection outcomes after vaccination in IIC versus non-IC individuals, rather than measuring vaccine effectiveness, to inform evidence-based decision-making regarding vaccination policies and public health strategies.

Materials and methods

Data source and study population

The Korea Disease Control and Prevention Agency-COVID-19-National Health Insurance Service (K-COV-N) cohort database was utilized for this study. This database integrates COVID-19 vaccination records, SARS-CoV-2 infection surveillance data, and health insurance claims data, providing a comprehensive view of the patient population. This study focused on individuals aged ≥ 12 years who had received at least one dose of the NVX-CoV2373 vaccine in South Korea between February 1 and December 31, 2022. These individuals were required to have at least 365 days of observation in the database prior to their vaccination date. Individuals with mixed primary series vaccinations (i.e., having received first and second doses of COVID-19 vaccines from different manufacturers) were excluded. In the third- and fourth-dose groups, individuals were included as long as their third or fourth dose was NVX-CoV2373, regardless of which COVID-19 vaccine was received for prior doses.

IIC were defined as those with conditions typically involving notable immune deficits or immunosuppressive treatments (but not intensive immunosuppressive therapies), using International Classification of Diseases, 10th Revision (ICD-10) codes documented in the two years prior to the index vaccination date. Conditions included rheumatologic or inflammatory disorder (L40–L45, M05–M14, G35, K50–K51); metabolic disorder (E10–E13; K90–K90.4); solid organ malignancy (C18, C22, C25, C34, C50, C53, C56, C64); chronic kidney disease (N18.1–6, N18.9); hematologic malignancy (C81–C96); organ or stem cell transplant (Z94.0–Z94.9); other intrinsic immune condition or immunodeficiency (D80–D84, D71, D73, Z90.81); HIV/AIDS (B20–B24) (Table 1 ). These conditions were included to generate a group of individuals representing a variety of potentially immunocompromising conditions. Although metabolic disorders are a heterogenous group, several conditions can be considered immunocompromising based on their impact on the dynamic interplay between the metabolic and immune systems [ 20 ] and increased susceptibility to infection/severe disease [ 21 ].

Outcomes

The primary outcomes of interest were any SARS-CoV-2 infection and severe SARS-CoV-2 infection. Severe infection was defined as either admission to an intensive care unit (ICU) due to SARS-CoV-2 infection or death following SARS-CoV-2 infection. ICU admissions were identified using specific treatment codes in conjunction with a primary or secondary diagnosis of conditions related to SARS-CoV-2 infection (ICD-10 codes: B342, B972, Z208, Z209, Z115, U181, Z038, U071, U072, U08, U09, and U10), as previously described [ 22 ]. Deaths occurring within 8 weeks of a confirmed SARS-CoV-2 infection were considered COVID-19–related, given the lack of precise cause-of-death data. COVID-19–related death was defined as death within 8 weeks of a positive test, consistent with national COVID-19 reporting criteria [ 23 , 24 ]. A sensitivity analysis was performed with data from a subset of participants considered severely immunocompromised, defined as those with records indicating solid organ malignancy; hematologic malignancy; rheumatologic or inflammatory disorder; or other intrinsic immune condition or immunodeficiency.

Statistical analysis

Our analyses were stratified by the dose of NVX-CoV2373 (i.e., primary series, third dose, or fourth dose), and descriptive baseline characteristics and demographics were provided for each group. Propensity score matching (1:1 match) was employed to balance baseline characteristics between enrolled IIC and a matched general population without an immunocompromised condition (i.e., non-IC) to minimize potential confounding. Balance was evaluated using absolute standardized difference (aSD) where an aSD > 0.1 indicated a significant difference. The propensity score was estimated using age, sex, region, prior SARS-CoV-2 infection, and comorbidity index as covariates. The matching was made as 1:1 nearest-neighbor matching without replacement, using a propensity score caliper to ensure well-matched pairs. Exact matching was completed on the year-month of vaccination. Relative risk was estimated using Cox proportional hazard models to produce adjusted hazard ratios (aHRs) and corresponding 95% CIs considering time-varying vaccination status. Date of NVX-CoV2373 vaccination was considered the index date (date of a second dose for the primary series). For the primary series group, the follow-up period for each individual began 14 days after the index date; for the analyses of third and fourth doses, the follow-up began 7 days after the index date. Follow-up continued through another 180 days, or until the earliest of the following events: documentation of SARS-CoV-2 infection, death, administration of a subsequent COVID-19 vaccine dose, or the end of the study period (December 31, 2022). The risk windows for evaluating outcomes were in 30-day intervals at 30, 60, 90, 120, 150, and 180 days after the start of follow-up. Time intervals of 30-days were selected to group sufficient events in each period and obtain more stable risk estimates. Regression models included adjustment for age at vaccination, sex, living in the non-capital area, presence of disability, employment, level of income, Charlson comorbidity index (CCI ≥3), obesity (body-mass index >30 kg/m 2 ), current smoker, and SARS-CoV-2 infection within 6 months prior to the index date.

A negative control analysis calculating adjusted odds ratios (aORs) and 95% CIs for any SARS-CoV-2 infection and severe infection during 0–5 days post-vaccination was performed using logistic regression. All statistical analyses were performed using SAS ® 9.4 software (SAS Institute, Cary, NC, USA), and the study protocol was approved by the Korea University Institutional Review Board (IRB No. 2024AN0084).

Results

Study populations

After excluding 168,106 non-homologous primary series doses, a total of 755,727 doses were administered to IIC (335,351 doses) and non-IC (420,376 doses) as homologous primary or homologous or heterologous third and fourth doses between February 1, 2022, and December 31, 2022 (Fig. 1 ). The immunocompromising conditions with the highest proportions of enrolled IIC were rheumatologic/inflammatory (56.0%) and metabolic (55.9%) disorders (Table 1 ).

Descriptive statistics showed that IIC, compared to the non-IC group, tended to be older, were more likely to be living in the non-capital area, had comorbidities or disability, were unemployed, and were medical aid beneficiaries (low/no income), whether they received NVX-CoV2373 as the primary series, third dose, or fourth dose (Table 2 ). After propensity score matching, the IIC and non-IC groups each had 31,958 participants in the primary series groups, 31,588 in the third-dose groups, and 211,420 participants in the fourth-dose groups (Fig. 1 ; Table 2 ). There was a significantly greater proportion of matched IIC compared with non-IC individuals who were aged 70–79 years and a significantly smaller proportion who were employed among recipients of a fourth dose (Table 2 ). No significant differences were observed between groups among primary series and third-dose recipients.

Incidence of SARS-CoV-2 infection

Infection incidence rate (IR) per 1000 person-days was determined among the IIC and non-IC populations across the defined risk windows. Among primary series recipients, the IR of any SARS-CoV-2 infection within the 30-day risk window (44–74 days post-vaccination) was 1.39 (95% CI: 1.32–1.47) for the IIC group and 1.32 (95% CI: 1.25–1.40) for the non-IC group (Table 3 ). During the same period, the IR (95% CI) for severe infection was 0.02 (0.01–0.03) for the IIC group and 0.02 (0.02–0.04) for the non-IC group. Through the 180-day risk window, the IR (95% CI) for any SARS-CoV-2 infection was 1.21 (1.18–1.24) and 1.10 (1.07–1.13) for the IIC and non-IC groups, respectively, and 0.01 (0.01–0.01) in both groups for severe SARS-CoV-2 infection.

For those who received a third dose of NVX-CoV2373, the IR (95% CI) for any SARS-CoV-2 infection was 2.19 (2.10–2.29) in both the IIC and non-IC groups within the 30-day risk window (Table 3 ). The IRs (95% CI) for severe infection in the IIC and non-IC groups in this period were 0.01 (0.01–0.02) and 0.01 (0.00–0.01), respectively. Within the 180-day risk window for the third-dose group, the IR (95% CI) for any SARS-CoV-2 infection in the IIC group was 1.08 (1.05–1.11) and 1.04 (1.01–1.07) in the non-IC group; the IRs for severe infection over the 180-day period were 0.01 (0.00–0.01) in both groups.

For those individuals who received a fourth dose of NVX-CoV2373, the IR (95% CI) within the 30-day risk window for any SARS-CoV-2 infection was 0.78 (0.76–0.80) in the IIC group and 0.76 (0.74–0.79) in the non-IC group and were 0.00 (0.00–0.01) in both groups for severe infection (Table 3 ). Within the 180-day risk window, the IRs (95% CI) for any SARS-CoV-2 infection were 0.68 (0.67–0.69) and 0.66 (0.65–0.67) for the IIC and non-IC groups, respectively, and for severe infection were 0.00 (0.00–0.00) in both groups.

Infection risk comparison among all IIC and non-IC individuals

Within the 30-day risk window after a primary series of NVX-CoV2373, any (aHR = 1.04 [95% CI: 0.96–1.12] or severe (0.72 [0.37–1.38]) SARS-CoV-2 infection did not significantly differ between groups of IIC and non-IC individuals (Table 3 ; Fig. 2 ). Through the 180-day risk window after a primary series, there was a significant and modestly higher risk (10%) for IIC, compared to non-IC individuals for any SARS-CoV-2 infection (aHR = 1.10 [95% CI: 1.06–1.14]), but not for severe infection (0.76 [0.52–1.12]). In this same window, there was a slightly increased significant risk of any infection post third dose (aHR = 1.05 [95% CI: 1.01–1.09]) and fourth dose (1.03 [1.02–1.05]) but no significant differences for severe infection. Overall, there was a slightly higher and significant risk of any SARS-CoV-2 infection in the fourth-dose group, across all risk windows.

Evaluation using the recently vaccinated period

The odds of any SARS-CoV-2 infection in the first 5 days after receipt of NVX-CoV2373 were slightly higher for IIC compared to non-IC individuals in the primary series group, and the difference was statistically significant (aOR = 1.21 [95% CI: 1.01–1.45]; Table S1). In this early period post vaccination, there was no significant difference in risk of any SARS-CoV-2 infection for IIC compared to non-IC individuals (aOR [95% CI]) in neither the third-dose group (1.13 [0.93–1.39]) nor in the fourth-dose group (1.09 [0.97–1.23]).

Sensitivity analysis of infection risk in subsets of IIC

Risk estimates for the 180-day risk window were stratified by the type of IIC (i.e., rheumatologic/inflammatory disorder, solid organ malignancy, hematologic malignancy, and organ or stem cell transplant), to assess a subset of individuals considered to have a more severe immunocompromising condition (Table S2).

A significantly higher risk of any SARS-CoV-2 infection was observed for individuals with a rheumatologic/inflammatory disorder across the primary series (aHR = 1.14 [95% CI: 1.09–1.19]), third-dose, and fourth-dose groups. Among individuals with a solid organ malignancy, there was no significant difference in risk of any SARS-CoV-2 infection, compared with non-IC individuals, after a primary series, third dose, or fourth dose of NVX-CoV2373. For individuals with a hematologic malignancy, risk estimates (aHR [95% CI]) were generally comparable to non-IC individuals; however, there was a significantly higher risk observed for any SARS-CoV-2 infection in the primary series group (1.27 [95% CI: 1.06–1.51]). IIC due to organ or stem cell transplant had a significantly higher risk of any SARS-CoV-2 infection in the primary series (aHR = 1.30 [95% CI: 1.06–1.60]) and fourth-dose groups compared with non-IC. Risk estimates for severe SARS-CoV-2 infection were also calculated for each IIC subgroup and are shown in Table S2.

Discussion

Across all dose groups and over the 180-day follow-up period, the risk estimates show that IIC had a slightly increased risk of any SARS-CoV-2 infection compared to non-IC individuals, with adjusted hazard ratios (aHRs) slightly greater than 1.0. The findings presented here have limitations (described below) and should be interpreted with caution. In the absence of an unvaccinated control group, we cannot directly measure absolute vaccine effectiveness (VE), and interpretation must rely on assumptions regarding the underlying risk of infection. Our data, including a significantly higher odds of any infection in IIC during the very early post-vaccination period (0–5 days) (aOR = 1.21 [95% CI: 1.01–1.45] in the primary series group), suggest that IIC have a higher baseline risk for medically attended infection compared to non-IC individuals. Supposing this similar or slightly increased baseline risk persists, the observed relative risk (aHRs close to 1.0) would actually suggest that NVX-CoV2373 provides comparable VE in IIC and non-IC people. Therefore, our results indicate that NVX-CoV2373 may offer meaningful protection to the IIC population, similar to the benefit observed in the general population. Notably, the gap in infection rates between IIC and non-IC groups decreased from ~10% after the primary series to ~3% after four doses, suggesting a meaningful improvement in protection for the IIC with additional doses.

Although risk differences were statistically significant in some instances, the clinical relevance of these marginal differences is not clear. Assessment of infection in the first five days post vaccination indicated significantly higher odds of any SARS-CoV-2 infection in IIC, compared to their non-IC counterparts after a primary series of NVX-CoV2373. The early post-vaccination increase suggests that IIC might have had a higher baseline risk for medically attended SARS-CoV-2 infection [ 25 , 26 ], or could have been more likely to seek healthcare, compared to those without an immunocompromising condition [ 27 ]. In an exploratory check, stratifying infection rates by age group in IIC, no clinically meaningful differences were identified. The group of IIC is very heterogeneous; therefore, a sensitivity analysis was performed to gather more information by examining infection in the 180-day risk window, in subsets of IIC with more severe immunocompromising conditions. Severe SARS-CoV-2 infections were assessed in the sensitivity analysis; however, the small sample size and low number of severe infections confound interpretation of these results.

The largest subgroup included in the sensitivity analysis comprised IIC with a rheumatologic/inflammatory disorder (56.0%). A small, but significantly increased risk of any SARS-CoV-2 infection was observed for all dose groups within this subgroup, compared to non-IC individuals; however, this subset of individuals is comprised of a heterogenous group of conditions and immune-modulating medications [ 28 ], which require a more in-depth analysis. Risk of SARS-CoV-2 infection was relatively similar between IIC with solid organ malignancy and the non-IC group across each of the dose groups. One reason for these comparable outcomes may be potentially less severe immunosuppression among those with solid organ malignancy, compared with other subgroups of IIC. Specifically, immune modulation is localized to the tumor microenvironment from targeted therapies [ 29 ] and chemotherapy treatment is shorter in duration (e.g., weeks/months) compared with life-long treatments for other conditions in IIC [ 30 – 32 ].

There was a statistically significant increase in risk (27%) of any SARS-CoV-2 infection in IIC with a hematologic malignancy compared with non-IC individuals in the primary series group. Considering that hematologic malignancies affect the bone marrow and production of lymphocytes, as does aggressive myelosuppressive treatment [ 33 ], these results are not surprising. Notably, in the OCTAVE-DUO study, participants with a hematologic malignancy who had low responses to a COVID-19 vaccine primary series were vaccinated with NVX-CoV2373 and had serological responses similar to those observed in healthy recipients of a primary series [ 34 ]. The results from the OCTAVE-DUO study, taken together with the general lack of significantly increased infection risk in the sensitivity analysis for this study, NVX-CoV2373 demonstrated relative impact in those with a hematologic malignancy.

Although only 0.5% of the IIC population in this study were individuals having undergone an organ or stem cell transplant, this subgroup was included in the sensitivity analysis based on their long-term/life-long use of immunosuppressive medications [ 35 , 36 ]. Results from this analysis indicate that individuals who have undergone an organ or stem cell transplant have significantly higher risk for any infection (~ 30% in the primary series and fourth-dose groups) compared with non-IC individuals. Despite the increased risk compared to non-IC individuals reported here, additional doses of COVID-19 vaccines are likely to afford some level of protection for this subgroup. For example, a study that included 30 kidney transplant recipients who had inadequate immune responses to four prior doses of mRNA-based COVID-19 vaccines reported seroconversion in 44% and robust immune responses in 17% of the population after receipt of a study dose of NVX-CoV2373 [ 37 ].

The population of IIC in this study encompasses conditions observed in the global population; however, the heterogeneity of conditions included can be considered a limitation with varying rVE among the different subgroups. The sensitivity analysis aimed to address concerns over heterogeneity by investigating outcomes in subsets of individuals considered to be severely immunocompromised; however, the low number of severe SARS-CoV-2 infections that occurred might have impacted the precision of analyzing that related risk within the condition subgroups, as well as in the overall population. Information on concomitant medications were unavailable, and these could have an impact on vaccine response and disease severity [ 38 , 39 ].

Propensity score matching and adjustments based on recent vaccination improved balance between the IIC and non-IC groups; however, the potential for additional confounders is a limitation. For example, IIC have a higher baseline risk of severe disease, which complicates interpretation of severe outcomes observed between groups. Furthermore, immunocompromising conditions vary widely with vaccine responses and impact potentially differing depending on the condition or treatment. Regarding matching, the hazard ratio between groups of IIC and non-IC individuals may be influenced by underlying differences in infection risk that persist after matching. Additionally, matching to non-IC individuals likely resulted in a ‘healthier’ population of IIC with fewer comorbidities, suggesting that the results reported here may be more applicable to IIC with a lower comorbidity burden.

The observed risk difference noted here may be a result of multiple factors (e.g., differences in exposure due to mask wearing or social distancing, vaccine effect, or medication) and the exact degree to which each of these factors contributed cannot be determined. Data on patients’ immunosuppressive therapy were unavailable, preventing analysis of vaccine impact by treatment, which is a limitation of this study. Additional factors within the subgroups may limit the generalizability of these findings. Specifically, the subgroup of individuals with chronic kidney disease likely comprises patients with advanced disease where those with early-stage chronic kidney disease are less likely to be immunocompromised; also, the small number of HIV cases suggests possible underreporting. An additional limitation is that the exact cause of death within 8 weeks of infection could not be confirmed and some may not be directly related to SARS-CoV-2 infection, which could affect the interpretation of the severe outcome results. Finally, this analysis includes only the prototype vaccine to ancestral SARS-CoV-2 (Wuhan), with data collection, including a period when variants were in circulation [ 19 ], and data are unavailable for which strains caused documented infections. Notably, a key strength of this study is the use of a large nationwide cohort and real-world data and that it is among the first to specifically evaluate NVX-CoV2373 performance in IIC, addressing an important gap in the current literature. The study period spanned different SARS-CoV-2 variant waves (e.g., BA.1/1.1, BA.2/2.3, and BA.5/5.2), which likely reduced vaccine effectiveness/impact. Nevertheless, these data indicate that NVX-CoV2373 was associated with reduced risk of SARS-CoV-2 infection in IIC (compared to vaccinated non-IC individuals), while acknowledging that no unvaccinated group was included to directly measure absolute vaccine effectiveness.

Conclusion

In conclusion, this real-world study showed that after NVX-CoV2373 vaccination, IIC had a slightly increased risk of SARS-CoV-2 infection compared to non-IC individuals across all dose groups. In the context of the study’s lack of an unvaccinated control group and the higher baseline risk of infection in the IIC population, this finding suggests comparable VE for NVX-CoV2373 between IIC and non-IC individuals in reducing the risk of SARS-CoV-2 infection.

A similar risk of medically attended SARS-CoV-2 infection between IIC and non-IC was observed with both a homologous primary series and homologous or heterologous third and fourth doses of NVX-CoV2373, as well as across a variety of immunocompromising conditions. However, findings for severe infection should be interpreted with caution due to the low number of events and resulting wide confidence intervals. These findings support prioritizing IIC in COVID-19 vaccination strategies as part of public health policy to protect high-risk populations.

Supplementary Information

Supplementary Material 1.

Acknowledgements

Medical writing and editorial support were provided by Kelly M. Fahrbach, PhD, CMPP, and Ebenezer M. Awuah-Yeboah, BS, of Ashfield MedComms (New York, USA), an Inizio company, supported by Novavax, Inc.

Abbreviations

adjusted hazard ratio

absolute standardized difference

immunocompromised

intensive care unit

individuals who are immunocompromised

incidence rate

recombinant spike

Authors’ contributions

EG, S-AC, MHG, MV, MDR, and YJC conceptualized the trial and contributed to its design.EG, S-AC, KK, and EB were involved in the extraction and analysis of data.EG, S-AC, KK, EB, MHG, JF, MV, MDR, and YJC were involved in the interpretation of data.EG, S-AC, KK, EB, and YJC verified the data.EG, S-AC, KK, EB, MHG, JF, MV, MDR, and YJC drafted the manuscript.EG, S-AC, and KK performed the statistical analyses.S-AC, MHG, JF, MDR, and YJC supervised the study.All authors critically reviewed and approved the manuscript content.

Funding

This work was supported by Novavax, Inc. The sponsor had primary responsibility for study design, protocol development, study monitoring, data management, and statistical analyses. All authors reviewed and approved the manuscript before submission.

Data availability

The data used in this study are from the K-CoV-N cohort, which is not publicly available. Researchers can apply for access to these data through the National Health Insurance Service (NHIS) and Korea Disease Control and Prevention (KDCA) data linkage system. Applications can be submitted via the Health Care Data Linkage (HCDL) website (https://hcdl.mohw.go.kr/) and are subject to review by the relevant authorities.

Declarations

Ethics approval and consent to participate

This study was carried out in accordance with the REporting of studies Conducted using Observational Routinely-collected Data (RECORD) guidelines and relevant local regulations. Patient consent forms and formal review by an institutional review board were not required for this type of research (Korea University Institutional Review Board exemption No. 2024AN0084).

Consent for publication

Written informed consent for publication from all participants whose data are included in this manuscript is not required for this type of research.

Competing interests

EG, SAC, KK, EB, and YJC are study investigators and do not have any conflicts of interest to report. JF, MHG, and MDR are employees of Novavax, Inc. and may own stock. MV was a salaried employee of Novavax, Inc. and may own stock.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Eunseon Gwak, Manuela H. Gschwend, Matthew D. Rousculp and Young June Choe contributed equally to this work.

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Associated Data

Supplementary Materials

Supplementary Material 1.

Data Availability Statement

The data used in this study are from the K-CoV-N cohort, which is not publicly available. Researchers can apply for access to these data through the National Health Insurance Service (NHIS) and Korea Disease Control and Prevention (KDCA) data linkage system. Applications can be submitted via the Health Care Data Linkage (HCDL) website (https://hcdl.mohw.go.kr/) and are subject to review by the relevant authorities.