key: cord-1008507-w8i7lbxw
authors: Kageyama, Takahiro; Ikeda, Kei; Tanaka, Shigeru; Taniguchi, Toshibumi; Igari, Hidetoshi; Onouchi, Yoshihiro; Kaneda, Atsushi; Matsushita, Kazuyuki; Hanaoka, Hideki; Nakada, Taka-Aki; Ohtori, Seiji; Yoshino, Ichiro; Matsubara, Hisahiro; Nakayama, Toshinori; Yokote, Koutaro; Nakajima, Hiroshi
title: Antibody responses to BNT162b2 mRNA COVID-19 vaccine and their predictors among healthcare workers in a tertiary referral hospital in Japan
date: 2021-08-08
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.07.042
sha: 8b487197468cc4f216047882817ad836a19507fb
doc_id: 1008507
cord_uid: w8i7lbxw

OBJECTIVES: This study aimed to determine antibody responses in healthcare workers who receive the BNT162b2 mRNA COVID-19 vaccine and identify factors that predict the response. METHODS: We recruited healthcare workers receiving the BNT162b2 mRNA COVID-19 vaccine at the Chiba University Hospital COVID-19 Vaccine Center. Blood samples were obtained before the 1(st) dose and after the 2(nd) dose vaccination, and serum antibody titers were determined using Elecsys® Anti-SARS-CoV-2S, an electrochemiluminescence immunoassay. We established a model to identify the baseline factors predicting post-vaccine antibody titers using univariate and multivariate linear regression analyses. RESULTS: Two thousand fifteen individuals (median age 37-year-old, 64.3% female) were enrolled in this study, of which 10 had a history of COVID-19. Before vaccination, 21 participants (1.1%) had a detectable antibody titer (≥0.4 U/mL) with a median titer of 35.9 U/mL (interquartile range [IQR] 7.8 – 65.7). After vaccination, serum anti-SARS-CoV-2S antibodies (≥0.4 U/mL) were detected in all 1,774 participants who received the 2(nd) dose with a median titer of 2,060.0 U/mL (IQR 1,250.0 – 2,650.0). Immunosuppressive medication (p<0.001), age (p<0.001), time from 2(nd) dose to sample collection (p<0.001), glucocorticoids (p=0.020), and drinking alcohol (p=0.037) were identified as factors predicting lower antibody titers after vaccination, whereas previous COVID-19 (p<0.001), female (p<0.001), time between 2 doses (p<0.001), and medication for allergy (p=0.024) were identified as factors predicting higher serum antibody titers. CONCLUSIONS: Our data demonstrate that healthcare workers universally have good antibody responses to the BNT162b2 mRNA COVID-19 vaccine. The predictive factors identified in our study may help optimize the vaccination strategy.

This study aimed to determine antibody responses in healthcare workers who receive the BNT162b2 mRNA COVID-19 vaccine and identify factors that predict the response.

We recruited healthcare workers receiving the BNT162b2 mRNA COVID-19 vaccine at the Chiba University Hospital COVID-19 Vaccine Center. Blood samples were obtained before the 1 st dose and after the 2 nd dose vaccination, and serum antibody titers were determined using Elecsys® Anti-SARS-CoV-2S, an electrochemiluminescence immunoassay. We established a model to identify the baseline factors predicting post-vaccine antibody titers using univariate and multivariate linear regression analyses.

Two thousand fifteen individuals (median age 37-year-old, 64.3% female) were enrolled in this study, of which 10 had a history of COVID-19. Before vaccination, 21 participants (1.1%) had a detectable antibody titer (≥0.4 U/mL) with a median titer of 35.9 U/mL (interquartile range [IQR] 7.8 -65.7). After vaccination, serum anti-SARS-CoV-2S antibodies (≥0.4 U/mL) were detected in all 1,774 participants who received the 2 nd dose with a median titer of 2,060.0 U/mL (IQR 1,250.0 -2,650.0). Immunosuppressive medication (p<0.001), age (p<0.001), time from 2 nd dose to sample collection (p<0.001), glucocorticoids (p=0.020), and drinking alcohol (p=0.037) were identified as factors predicting lower antibody titers after vaccination, whereas previous COVID-19 (p<0.001), female (p<0.001), time between 2 doses (p<0.001), and medication for allergy (p=0.024) were identified as factors predicting higher serum antibody titers.

J o u r n a l P r e -p r o o f Introduction BNT162b2 mRNA vaccine against COVID-19 has shown promising efficacy both in a clinical trial [1] and in nationwide mass vaccination settings [2] . The vaccine has also shown short-term efficacy in a large-scale prospective cohort study targeting healthcare workers, a population that should be prioritized for vaccination [3] ; however, the factors that predict the effectiveness of BNT162b2 mRNA vaccine have not been fully explored.

As the humoral responses have been shown to play essential roles in the protection against and the survival from SARS-CoV-2 infection [4] [5] [6] , the antibody status after vaccination can provide important information to predict long-term effectiveness and to optimize the vaccination strategy. However, antibody responses after vaccination have been assessed only in small-scale studies [7] [8] [9] [10] [11] [12] . Here, we report the antibody responses and their predictive factors in 2,015 healthcare workers who received the BNT162b2 mRNA COVID-19 vaccine. We first performed univariate linear regression analyses to identify factors associated with the serum anti-SARS-CoV-2S antibody titer after vaccination. We next performed a multivariate linear regression analysis with a stepwise method using factors that showed a pvalue <0.1 in univariate analyses. Statistical analyses were performed using SPSS version 23.0 (IBM, Armonk, NY). A two-sided p-value <0.05 was considered statistically significant.

The study procedures for sample collection and those for analyses were approved by Chiba University Ethics Committee on February 24 th , 2021 (No. HS202101-03) and April

Out of 2,838 employees in Chiba University Hospital, 2,549 (89.8%) received at least one dose of BNT162b2 mRNA COVID-19 vaccine (30 µg) from March 3 rd to April 9 th , 2021, and 2,015 individuals (71.0%) were enrolled in this study. Demographics and background information are summarized in Table 1 . Table 1 . The factors retained in the final multivariate model (adjusted R 2 0.188) were immunosuppressive medication, age, time from 2 nd dose to sample collection, previous COVID-19, sex, time between 2 doses, glucocorticoids, medication for allergy, and drinking alcohol ( Figure 1 ).

All subjects who received 2 doses of BNT162b2 mRNA COVID-19 vaccine had a detectable level of serum anti-SARS-CoV-2S antibody, and all but one subject who were seronegative before vaccination became seropositive (99.9%). In addition, all of 18 subjects who were already seropositive before vaccination showed substantial antibody responses after the 2 nd dose. These results are consistent with previous smaller-scale studies [7, 8, 11, 12] and indicate that the vast majority of young-adult healthcare workers have good antibody responses following 2 doses of the BNT162b2 vaccine.

The large sample size of our study allowed for establishing a stable multivariate model to determine background factors that predict antibody responses. The strongest and the most significant factor was receiving immunosuppressive drugs. Receiving glucocorticoids was also identified as an independent predictor even though our study population was mostly healthy workers and only 14 (0.9%) and 9 (0.6%) were taking glucocorticoids and immunosuppressant, respectively. Our data confirm the results of previous studies which demonstrated reduced antibody responses among patients on immunosuppressive regimens [13] .

Unexpectedly, medication for allergy was also identified as a factor significantly associated with higher antibody titers. Although we have no information on the drug and diagnosis for the medication, we speculate that the majority were taking anti-histamine drugs for cedar pollen allergy, which is very common in Japan in spring. Interestingly, some studies have suggested potential therapeutic effects of histamine H1 receptor antagonists on COVID-19 [14] . Together with alcohol consumption as a negative predictor, these novel associations deserve further investigation.

While only 10 participants (0.5%) in our study had a history of COVID-19, it was the fourth most significant factor in our multivariate model. Its influence might have been J o u r n a l P r e -p r o o f underestimated since 2 participants who had the highest titers did not have a history of previous COVID-19 but both were seropositive before vaccination, and one had had close contact with an infected individual. Again, this result is consistent with previous reports [11, 12, 15, 16] and consolidates the evidence that the BNT162b2 vaccine induces more robust antibody responses in individuals previously infected with SARS-CoV-2.

Among demographic factors, older age has been repeatedly reported to associate with reduced antibody responses after COVID-19 vaccination [7, 8, 11, 12] . Our study population is younger than those in previous studies and supplement the evidence. Sex difference has also been reported to associate with antibody responses to various degrees [8, 11, 12] . Our large-scale data confirm the notion that women tend to have a greater antibody response to the BNT162b2 vaccine than men.

Our study has some limitations. First, this is a single-center study in Japan with mostly Japanese subjects. Second, neutralizing activity was not measured. However, the assay we employed has been shown closely correlated with the titer of neutralizing antibody [17] , and 99.5% of our study subjects achieved a serum antibody level above the cut-off of 

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We thank all staff in Chiba University Hospital for supporting sample collection.

We have no conflict of interest to declare.