key: cord-0078846-8zb0afol
authors: Kim, Min Hyung; Nam, Yooju; Son, Nak-Hoon; Heo, Namwoo; Kim, Bongyoung; Kang, Eawha; Shin, Areum; Yang, Andrew Jihoon; Park, Yoon Soo; Kim, Heejung; Kyong, Taeyoung; Kim, Yong Chan
title: Antibody level predicts the clinical course of breakthrough infection of COVID-19 caused by delta and omicron variants: a prospective cross-sectional study
date: 2022-05-20
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofac262
sha: 7434e05817cae6a1286cf2f7044f395f3b511567
doc_id: 78846
cord_uid: 8zb0afol

BACKGROUND: Omicron variant viruses spread rapidly, even in individuals with high vaccination rates. This study aimed to determine the utility of the antibody against the spike protein level as a predictor of the disease course of COVID-19 in vaccinated patients. METHODS: Between 11 December 2021 and 10 February 2022, we performed a prospective observational cohort study in South Korea, which included patients infected with delta –and –omicron variants. Multivariable logistic regression analysis to determine the association between antibody levels and the outcomes was conducted.The relationship between antibody levels and cycle threshold (Ct) values was confirmed using a generalised linear model. RESULTS: From 106 vaccinated patients (39 delta and 67 omicron), the geometric mean titres of antibodies in patients withfever (≥37.5 °C), hypoxia (≤94% of SpO(2)), pneumonia, C-reactive protein (CRP) elevation (>8 mg/L), or lymphopenia (<1,100 cells/μL) were 1,201.5 U/mL, 98.8 U/mL, 774.1 U/mL, 1,335.1 U/mL, and 1,032.2 U/mL, respectively. Increased antibody levels were associated with a decrease in the fever occurrence (adjusted odds ratio [aOR], 0.23; 95% confidence interval [CI], 0.12–0.51), hypoxia (aOR, 0.23; 95% CI, 0.08–0.7), CRP elevation (aOR, 0.52; 95% CI, 0.29–0.0.94), and lymphopenia (aOR, 0.57; 95% CI, 0.33–0.98). Ct values showed a positive correlation between antibody levels (P =0.02). CONCLUSION: Antibody levels are predictive of the clinical course of COVID-19 in vaccinated patients with delta and omicron variant infections. Our data highlight the need for concentrated efforts to monitor patients with SARS-CoV-2 infection who are at risk of low antibody levels.

established by vaccination, resulting in increased infectivity [3, 4] . In addition, a decrease in 7 immunity elicited by vaccines over time, namely waning immunity, may play an important 14 In South Korea, owing to quarantine and isolation guidelines, it took more time for the 15 omicron variant to become the dominant strain than in other countries. According to several 16 reports, the omicron variant virus presumably has weakened virulence, which is related to 17 reduced severity, hospitalisation, and mortality [7, 8] . However, the recent explosive increase 18 in the number of omicron variant infections has increased the total number of deaths, and the 19 omicron's spread has not slowed as of 28 February 2022. In this situation, to efficiently use 20 limited medical resources, it is important to predict which patients will go through an 21 unfavourable clinical course and put concentrated efforts into them. 22 We performed a prospective cross-sectional study involving patients with delta and omicron 23 variant infections who were admitted to an institution in South Korea. This study aimed to 1 Furthermore, we evaluated the usefulness of the antibody level to spike protein as a predictor 2 of the disease course of COVID-19 in vaccinated patients. 3 Methods 4 Study design and participants 5 We performed a prospective cross-sectional study involving SARS-CoV-2 confirmed adult 6 patients (age, >19 years) who were admitted to the Yongin Severance Hospital. All SARS-7 CoV-2 cases were confirmed by polymerase chain reaction (PCR) tests at government 8 approved test centres and then notified to a local public health centre in South Korea. Patients 9 with specified symptoms or conditions were asked to be hospitalised for monitoring and 10 treatment, and they were assigned to appropriate hospitals according to their severity of 11 COVID-19 if they were willing to do so. Symptoms and conditions for which hospitalisation figure 1 ). Patients who agreed to undergo PCR tests for the SARS-CoV-2 variant type and 22 anti-SARS-CoV-2 antibody tests were eligible for enrolment in this study. Only participants 23 with confirmed delta or omicron variant infections were included in the analysis. 1 We collected data on initial symptoms, reinfection identified via a questionnaire, diagnosis 2 date, initial PCR cycle threshold (Ct) value, COVID-19 vaccination history, and household The study's primary outcomes were to compare patients with delta and omicron variant 

2 Only patients who were tested for antibody levels within 7 days of symptom onset or 3 diagnosis, whichever was earlier, were included in the analyses using antibody titres. The 7-4 day period was designated to minimise the effect of current infection on antibody levels 5 elicited by vaccination [11] . Furthermore, we performed sensitivity analyses using 3-day and 6 5-day thresholds. We investigated viral dynamics using Ct values obtained from the PCR test. 7 Viral dynamic analysis was conducted only on data from patients who had undergone the 8 PCR test-5-7 days after the initial diagnosis. Continuous variables were analysed using descriptive methods depending on their 10 distribution and tested using the Shapiro-Wilk test. Variables with a normal distribution were 11 described as means and standard deviations, and independent two-sample t-tests were 12 performed. Non-normal variables were expressed as medians and interquartile range (IQR). Figure 1A ). Antibody levels were tested at a median of 4 days (IQR 2-6) of symptom onset 14 or diagnosis, and variant-type assays were performed at 4 days (IQR 3-5) after the initial 15 diagnosis ( Figure 1B ). 16 Of the 161 patients who had the delta or omicron variant infection, 85 (53 %) were women, Table 3 ). Unvaccinated or partially vaccinated patients (n=50) more commonly experienced 9 fever, pneumonia, or hypoxia during hospitalisation than vaccinated patients did. Vaccinated 10 patients had a shorter time to defervescence than unvaccinated or partially vaccinated ones.

Laboratory results did not differ between the vaccinated and unvaccinated or partially Table 4 ).

When we classified vaccinated patients with delta and omicron variant infection into booster-16 vaccinated (n=47) and booster-unvaccinated (n=64) groups, as expected from a recent 17 national vaccination program recommending a booster shot, the time since the last 18 vaccination to confirm SARS-CoV-2 infection was shorter in the booster-vaccinated group 19 than in the booster-unvaccinated group. Symptoms, signs, laboratory results, and treatment 20 drugs, except for dexamethasone, did not differ between groups (Supplementary Table 5 ). Tables 6-9 .

Data from 106 patients whose serum samples were collected within seven days of symptom 1 onset or diagnosis were used for analyses using antibody titres ( Figure 1B ). The geometric 2 mean antibody titres in patients who experienced fever, hypoxia, pneumonia, CRP elevation, 3 and lymphopenia during hospitalisation were 1,201.5 U/mL, 98.8 U/mL, 774.1 U/mL, 4 1,335.1 U/mL, and 1,032.2 U/mL, respectively, which were lower than those in patients who 5 did not (Supplemental table 10 and Figure 2 ). Similar results were observed when the 6 selected patients were divided into delta and omicron variant infection groups. Sensitivity 7 analyses using 3-day and 5-day thresholds for time since symptom onset or diagnosis to 8 antibody test did not differ from the main analyses ( Supplementary Figures 2 and 3) . 17 Therefore, we investigated the association between antibody levels and viral dynamics.

Among 106 patients included in the analyses using antibody levels, 33 patients who had Ct 19 values from the PCR tests 5-7 days after the initial diagnosis were selected. Patients with 20 higher antibody levels had higher Ct values at 5-7 days after the initial diagnosis, indicating 21 lower viral loads than those with lower antibody levels (p=0.022) (Figure 3 ). We also 22 evaluated the association between antibody levels and Ct values at the initial diagnosis.

Although several different commercial PCR kits were used at initial diagnosis because the 24 patients were tested in different institutions at the time of diagnosis, we found no difference Table 5 ,7,9). However, (Table 1) . 12 However, in breakthrough infections caused by delta and omicron variants, the variant type 13 was not associated with the occurrence of specific signs observed in this study, except for 14 pneumonia (Table 2) . We assume that our findings are owing to the reduced effectiveness of 15 vaccines against omicron variants. Indeed, the omicron variant has multiple mutations that 16 enable evasion of the vaccine-induced immune system [19, 20] . A decrease in immunity infection, although it relied on self-reporting. Furthermore, our findings were robust in a 10 sensitivity analysis involving patients who tested antibody levels within 3 or 5 days of 11 symptom onset or diagnosis. Second, since our study hospital has specific criteria for 12 admission, which allowed only patients with mild to moderate severity to be admitted, we 13 could not investigate the effects of antibody levels on outcomes such as moving to the severe 14 phase (n=2) or death (n=0). Therefore, further studies involving a larger number of patients 15 with a wide range of disease severity are warranted. Third, the diagnosis of pneumonia in this 16 study was based on chest radiographic findings. Chest radiography is limited in its ability to 17 detect subtle pneumonia. Furthermore, we did not routinely perform follow-up chest 18 radiography if the initial test did not report abnormal findings and if the patient's condition 19 did not change. Therefore, the results associated with pneumonia should be cautiously 20 interpreted. Fourth, we did not consider the type of vaccine (e.g. adenoviral vector-based, vaccines. In this regard, we did not classify the participants according to the type of vaccine 3 but only vaccination status to reflect real-world population data. Lastly, we explored the 4 relationship of antibody levels with individual variable associated with poor outcomes instead 5 of collective variables that predict adverse outcome. Since there is no consensus on the 6 validity of the scoring system in predicting outcomes, we determined not to use it.

In conclusion, this study showed the significance of antibody levels as a predictor of the 8 clinical course of COVID-19 in patients with breakthrough infections caused by delta and 9 omicron variants. Moreover, in our study, enhanced viral clearance was observed in 10 vaccinated patients with higher antibody levels than in those with lower antibody levels. We 11 highlight the need for concentrated efforts to monitor patients with SARS-CoV-2 infection 12 who have conditions related to poor antibody response to vaccination (e.g. 13 immunocompromised status) or waning immunity after vaccination (e.g. adenoviral vector-14 based vaccine) since they are more likely to undergo an unfavourable disease course. Acknowledgments. We would like to thank all of the nursing and laboratory staff as well as 17 the physicians who supported this project. Finally, we give credit to all of the patients who 18 took part in this study. 19 Potential conflicts of interests The authors declare that they have no competing interests.

Funding support. This research received no specific grant from and funding agency, 21 commercial or not-for-profit sectors. 22 Availability of data and materials. The dataset supporting the conclusions of this article is 23 included within Supplemental data (Appendix 2. Raw data used in the analysis). 

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Antimicrobial agents, n (%)