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Peculiarities of Humoral Immunity Formation in Medical Institution Employees Recovered from or Vaccinated against COVID-19 in Irkutsk

We performed a seroepidemiological survey of the level and structure of population immunity to SARS-CoV-2 among employees of medical institution in the Irkutsk region during the COVID-19 pandemic. Seroprevalence assessment was organized from May 2020 to April 2021. The level of antibodies to SARS-CoV-2 was measured by ELISA. It was found that 139 (46%) of 299 examined workers were seropositive, including 50 (36%) vaccinated against COVID-19, 75 (54%) patients diagnosed with COVID-19, and 14 (10%) asymptomatic cases of SARS-CoV-2. The results obtained should be taken into account when predicting the dynamics of the epidemic process and organizing preventive (antiepidemic) measures, including vaccination.

The new COVID-19 infection has become not only the global health problem, but also the most serious challenge for the global community in the 21st century. Within 3 months since the first detection in China (Wuhan) in December 2019, the new coronavirus has rapidly spread around the world, and on March 11, 2020, the WHO declared COVID-19 a pandemic [1,7]. According to official data, as of April 2021, more than 136.6 million cases of COVID-19 infection and more than 2.9 million deaths were registered in the world [3,5]. In the Russian Federation, cases of COVID-19 have been registered since January 31, 2020. More than 4.6 million cases of SARS-CoV-2 infection have been laboratory confirmed in the Russian Federation in all regions of the country and more than 101,000 deaths from this disease have been registered at the moment of writing this article (April 2021) [3,5].
The emergence and spread of COVID-19 have set the priority tasks for healthcare professionals to quickly diagnose and organize qualified medical care for patients, which can only be solved with a clear understanding of the features of the immunogenesis of a new coronavirus infection, in particular, the relationship between the severity of the disease and the kinetics of the antibody response. For example, a number of articles support the finding that people with more severe COVID-19 who needed care in intensive care units seroconverted earlier than those with milder disease [9,10]. A significant role in the pathogenesis of COVID-19 is played by the characteristics of the patient's immune system. It is known that an insufficiently rapid response of innate immunity to the introduction of the SARS-CoV-2 virus leads to its longterm persistence, which determines the abnormally long duration of the infectious process and the risk of dangerous mutations [2,4,8,12].
An important role in the fight against COVID-19 is assigned to the study of population immunity to SARS-CoV-2, in particular the dynamics of seropre-valence and the formation of post-infection humoral immunity. This knowledge is necessary for developing programs and interpreting the results of seroepidemiological studies, scientific forecasting of the development of an epidemic situation, evaluating the effectiveness of vaccination, and planning the preventive and anti-epidemic measures [6,11].
Our aim was to study the dynamics of the formation of specific antibodies to the SARS-CoV-2 virus and the duration of their persistence in recovered and vaccinated subjects, healthcare institution workers in the Irkutsk region.

MATERIALS AND METHODS
The detection of specific antibodies to the SARS-Cov-2 virus was carried out in dynamics, during the epidemic outbreak in the Irkutsk region from May 2, 2020 to April 5, 2021, every 25-30 days in a healthcare institution in Irkutsk. In total, the study involved 299 volunteers (117 men and 182 women) aged 20-39 years (n=129), 40-59 years (n=104), and ≥60 years (n=66). All surveyed subjects were divided into the following groups: patients with laboratory-confirmed COVID-19 (n=82) and asymptomatic course of the disease (n=14), vaccinated workers (n=60) with negative tests for SARS-CoV-2 virus RNA (PCR) and specific antibodies to the virus (ELISA) at the time of vaccination, and "conditionally healthy" subjects (n=143). The study followed the ethical principles of the Declaration of Helsinki of the World Medical Association. The study was approved by the Local Ethics Committee of the Irkutsk Antiplague Research Institute (Protocol No. 7, November 15, 2021).
Specific IgG were determined by ELISA using a commercial kit for the analysis of human serum or plasma for the presence of IgG antibodies to the nucleocapsid (N-protein SARS-CoV-2; State Research Center for Applied Microbiology and Biotechnology, Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing) and to surface S-glycoprotein of the virus (SARS-CoV-2-Ig G-ELISA-BEST; Vector-Best). In additionally, IgG antibodies to the receptor-binding domain of the surface glycoprotein S (spike) of the coronavirus were detected using SARS-CoV-2-RBD-ELISA-Gamaleya kits in the serum of volunteers vaccinated with Gam-COVID-Vac and IgG antibodies to coronavirus proteins were detected using SARS-CoV-2-IgG-Vector kits (State Research Center of Virology and Biotechnology VECTOR) in subjects vaccinated against COVID-19 with EpiVacCorona vaccine.
The measurements were performed on a Stat Fax 4200 semi-automatic analyzer of enzyme-linked immunosorbent reactions (Awareness Technology) by absorption at λ=450 nm; the results were considered positive at positivity index (PI)≥1 (calculated according to instructions of kits manufacturers).
The study employed epidemiological (descriptive and analytical) and statistical methods. Statistical processing was performed using the methods of variation statistics (Microsoft Excel). The differences were significant at p<0.05.

RESULTS
In the surveyed group, 82 (27%) workers had COVID-19 until April 5, 2021, of them 68 (23%) subjects had manifest disease in the form of an acute respiratory infection or community-acquired pneumonia and 14 (5%) cases were asymptomatic. The first 4 cases of the disease, unrelated to each other, were registered in May, the maximum number of cases fell on October, and then, the number of cases decreased to single cases in February, which coincided with the dynamics of the epidemics in Irkutsk (Fig. 1).
Seroprevalence did not differ in men and women (91 and 92%, respectively). The age structure of seroprevalence was heterogeneous and varied from 89% (age group 20-39 years) to 96% (in the group ≥60 years) ( Table 1).
When assessing the time of the appearance of specific antibodies to the SARS-CoV-2 virus, we found that IgG were detected starting from the 6th day from the moment of diagnosis (Fig. 3). During the period from day 25 to 175 from the disease onset, the proportion of seropositive subjects was 70% (n=57). In some cases, the surveyed showed a decrease of the production of specific IgG to the SARS-CoV-2 nucleocapsid starting from day 150 after the diagnosis.
The number of volunteers diagnosed with COVID-19 who have specific IgG to the SARS-CoV-2 nucleocapsid during the observation period was 75 (92%), while 16 previously seropositive persons have registered the decline of PI below the reference value (PI<1.0) by April 2021. At the same time, IgG to the SARS-CoV-2 virus glycoprotein was detected in all seropositive volunteers at all follow-up periods. It was also noted that 7 subjects diagnosed with COVID-19 had no antibodies to SARS-CoV-2 nucleocapsid or glycoprotein.
IgM production in recovered workers was detected at the early stage (days 5-6) and persisted up to day 45 after diagnosis.
The research results showed that seroconversion among medical institution employees after vaccination with EpiVacCorona was recorded in 34 (69%) people, starting from days 42-44 after primary immunization (in case of Gam-COVID-Vac vaccine starting from day 45). It is important to note that specific IgG antibodies to the proteins of the SARS-CoV-2 coronavirus, and to the nucleocapsid and glycoprotein of the SARS-CoV-2 virus were not detected in 10 (20%) volunteers vaccinated with EpiVacCorona. At the same  time, all vaccinated with Gam-COVID-Vac had specific antibodies to the receptor-binding domain of the surface glycoprotein S of the SARS-CoV-2 coronavirus. Thus, the epidemiological patterns of the spread of COVID-19 in a single group were characterized by an undulating course and a low intensity of the outbreak, with 27% of the group being involved in the epidemic process from May 2020 to March 2021. It is important to note that none of the study participants had repeated cases of the disease during the entire observation period despite the continuing unfavorable situation with COVID-19 in the Irkutsk region. And there were no cases of an unfavorable outcome of the disease. The level of herd immunity among volunteers of the institution during the development of the epidemic was characterized by an upward trend and at the time of the research (May 4, 2021) it was 46.5% (139/299). The current results of serological monitoring serve as a scientific basis for adjusting the list and scope of anti-epidemic (preventive) measures in a single team, in particular, for planning vaccination against COVID-19.
The authors of this article report no conflicts of interest.
The planning of the experiment, the analysis of the results, and the writing of the article were carried out by V.