key: cord-0878139-w18jiixp
authors: Dundar, Bagnu; Karahangil, Kadriye; Elgormus, Cagri Serdar; Topsakal, Hatice Nur Halipci
title: Efficacy of antibody response following the vaccination of SARS‐CoV‐2 infected and noninfected healthcare workers by two‐dose inactive vaccine against COVID‐19
date: 2022-02-14
journal: J Med Virol
DOI: 10.1002/jmv.27649
sha: d63f39a0ac9ea6941cf266384fd17a79ff9a7c6e
doc_id: 878139
cord_uid: w18jiixp

Sinovac is an inactive vaccine produced against Coronavirus Disease 2019 (COVID‐19) for almost a year. No sufficient information is available concerning pro‐vaccine immunogenicity. We investigated the efficacy of antibody response following vaccination of SARS‐CoV‐2‐infected and noninfected healthcare workers by a two‐dose inactive vaccine against COVID‐19. The immunogenicity acquired on the 27th day and 42nd day after the first dose of vaccine (corresponding to Day 14 after the second dose) were compared by the demographics, immunosuppression, comorbidities, postvaccination reaction, and IgG levels of 120 subjects. The overall rate of second postvaccine seropositivity was 97.5% (n = 117) of all individuals, and 44 of these were seropositive after the first dose. The percentage of having a previous COVID‐19 (59.1%) among seropositive individuals before 2nd vaccination was significantly higher than those of seropositive individuals (10.96%) after second vaccination (p < 0.0001). In our study, 35 healthcare workers stated that they had previously had a COVID‐19 infection. Anti‐SARS‐CoV‐2 antibody responses in people infected with SARS‐CoV‐2 follow a classical pattern, with a rapid increase within the first 3 weeks after the appearance of symptoms. Although the titers decreased thereafter, the ability to detect anti‐SARS‐CoV‐2 IgG antibodies supports the view that the majority of subjects previously screened as positive for virus remain intact with confirmed neutralizing activity for up to 6 months.

administered to the healthcare workers in our country as in many countries. 1, 2 Several vaccines developed and produced based on the completed vaccine studies have been validated by World Health Organization (WHO) for emergency use considering the public health criteria and administered firstly to the privileged groups. 3 The vaccine administered in Turkey since January 2021 is a purified, inactivated, and adsorbed COVID-19 vaccine developed by Sinovac Biotech Corporation. 4 Sinovac, with a pharmaceutical name CoronaVac and previously known as PiCoVacc, was developed by propagating the SARS-CoV-2 CN2 strain inside Vero Cells and inactivating it with B-propiolactone. In preclinical trials, Sinovac induced SARS-CoV-2specific neutralizing antibodies (NAbs) in rats, mice, and the rhesus macaque. 5 The antibodies were found to neutralize 10 representative SARS-CoV-2 strains. As of August 2020, the vaccine has been tested in numerous human clinical trials assessing its safety and immunogenicity and Phase-3 studies have been ongoing. 6 Many vaccination platforms use a two-dose prime-boost approach for forming an immune response against the virus S1 spike protein, of which titers are related to functional virus neutralization and are increased by augmentation. To provide the first dose of vaccine to more people, the delayed administration of the second dose is asserted in a limited number of studies reflecting the vaccine results. [7] [8] [9] Also, the number of studies showing the effect of the vaccination in SARS-CoV-2-infected subjects who already had an immunity-enhancing condition is limited. [10] [11] [12] In this study, we aimed to assess the new phase of the struggle against COVID-19 by presenting the immunization formed in the healthcare workers after vaccination by two doses of Sinovac. We discussed the efficacy of a second dose since the first vaccine dose would also effectively support the individuals who had already been infected by the SARS-CoV-2. To test the hypothesis, we determined the antibody response developed at the 27th and 42nd days of first vaccination in 120 healthcare workers for whom two doses of Sinovac administration were completed.

This study was conducted on 120 healthcare workers working in 

Whole blood was drawn from the participants by using the vacuum blood collection method on the 27th day after the first vaccination and on the 14th day after the second vaccination (corresponding to Day 42 of the first dose). The samples were taken to silicon tubes including micronized silica particles and serum separator to accelerate blood coagulation. The blood samples were left for 30 min at room temperature before centrifugation. They were centrifuged at 20-25°C at 1300-2000g for 10 min. In the serum samples obtained, IgG antibody levels produced against receptor-binding domain (RBD) protein of SARS-CoV-2 S1 was measured by the method given below. 

All statistical analyses were performed by using GraphPad InStat 

The mean age of the participants was 37.19 ± 11.33 and most of them were female (63.3%). In total, 16.7% of participants were immunosuppressed and 22.5% had at least one comorbidity, including hypertension, diabetes asthma, allergy, and malignancy (Table 1) .

Thirty-six individuals (30%) had a previous COVID-19 before vaccination. One patient was excluded from the negative patient group because it was not known whether she had COVID-19 ( Table 2 ). Comparison of the demographic and serological data between individuals with or without COVID-19 before vaccination showed that the mean age, distribution of gender, mean BMI, the frequency of immunosuppression and comorbidities, and occurrence of postvaccination reaction did not differ among the two groups.

However, the mean IgG levels of the positive COVID-19 group after the first dose of vaccination were significantly higher than those of the negative group (p < 0.0001), while the mean IgG levels after the second dose were comparable between groups. The absolute change and the percent change were significantly higher in the negative COVID-19 group compared to those in the positive group (p < 0.0001) ( Table 2) .

Comparison of the demographic and serological data according to the seroconversion results are shown in Table S1 . The antibody positivity rate after two doses of vaccine was detected as 97.5%. One hundred and seventeen individuals achieved a seroconversion after two doses of vaccination, while three individuals were IgG negative on the 42nd day after two doses of vaccine, although they were not immunosuppressive and did not have any comorbidity. Two of these individuals whose absolute change and percent change in IgG levels were lower than those of immunized individuals had a previous COVID-19 before vaccination, but did not show any difference in the demographics compared to immunized individuals. In other words, seroconversion did not occur in 5.6% of 36 individuals who had a previous COVID-19 before the vaccination (Table S1 ).

Comparison of the demographic and serological data between individuals before and after the second vaccination is listed in Table S2 . A total of 36.7% of all participants had the antibody positivity before the second vaccination, while 60.8% turned seropositive after the second dose. The individuals who were seropositive before the second vaccine were significantly younger than those who were seropositive after the second dose (p = 0.0001). There was no sig- It has been stated that an additional dose may be required up to 6 months after two doses of vaccine for boosting the efficacy. 15 Another study evaluated the tolerability and immunogenicity of recombinant adenovirus type 5 (Ad5-vectored vaccine against COVID-19) expressing the spike protein of SARS-CoV-2 strain and determined that the antibodies increased significantly on the 14th day and peaked 28 days after the vaccination. 16 Therefore, we The biggest limitation of the present study is the small sample size, which may be considered as not enough to conclude that previous infection may post the seroconversion. Another limitation is the lack of measurement of the level of antibodies in both infected and not infected groups before vaccination. The general challenge of studies related to COVID-19 diseases is that it is not confirmed that COVID-negative patients were not infected before; however, individuals who did not show any symptoms in the general course of the disease were considered COVID-negative, but there is still a possibility that these people had the disease without showing any symptoms (asymptomatic). However, the findings of this study suggest that the second dose of Sinovac posts the immune response in naïve vaccinated individuals. The last limitation is that an evaluation was not performed for the patients who had the disease as the healthcare workers with a history of disease might be infected at different times and the results of prevaccination antibody levels were not available.

One of the major challenges for the commercially available serology assays is that their binding antibody results are provided in arbitrary units per milliliters (ARU/ml). Thus, the results between assays are highly variable, although they target the same SARS-CoV-2

antigen. In our study, the antibody levels were presented as index units and it corresponds to 21.8 binding antibody unit/ml (BAU/ml) according to the standards determined by the kit manufacturer.

However, there are reports stating that the BAU can be correlated with the level of NAbs. 21, 22 As a result, this study demonstrated that a previous COVID-19 in healthcare workers may boost the seroconversion even at the first dose of vaccination by Sinovac if they were infected previously. Anti-S protein levels may contribute to the percent change in IgG levels of naïve vaccinated individuals and may be considered as a determinant in vaccination. Future studies are required to determine the amount of anti-S protein of the subjects to be vaccinated; therefore, the number of booster shots can be determined.

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The authors also thank the equipment provider of SIEMENS ADVIA Centaur XP Immunoassay System for the test kits.

The authors declare that there are no conflict of interests.

The study protocol was approved by the Non-Interventional Scientific Research Ethical Committee of Istanbul Atlas University (Date: 

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. | 2437