SARS-CoV-2 Herd Immunity of the Kyrgyz Population in 2021

doi:10.21203/rs.3.rs-1138128/v1

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SARS-CoV-2 Herd Immunity of the Kyrgyz Population in 2021

https://doi.org/10.21203/rs.3.rs-1138128/v1

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Background. In the fight against coronavirus infection, an important direction is control of herd immunity to the pathogen. SARS-CoV-2 herd immunity is formed naturally as a result of manifest or asymptomatic infection, or artificially as a result of vaccination

Aim: To assess the SARS-CoV-2 herd immunity status of the Kyrgyz population.

Materials and methods. A cross-sectional, randomized study of SARS-CoV-2 herd immunity was carried out according to a program developed by Rospotrebnadzor, with the participation of the Saint Petersburg Pasteur Institute, taking into account WHO recommendations. In all study stages cloud service (internet) technologies were used. The ethics committees of the Preventive Medicine Association (Kyrgyzstan) and the Saint Petersburg Pasteur Institute (Russia) approved the study. A total of 9,471 volunteers were selected, representing 0.15% (95% CI 0.14-0.15) of the total population. They were randomized according to age and region. Antibodies (Abs) to the nucleocapsid antigen (Nag) were determined by enzyme-linked immunosorbent assay (ELISA) of volunteer blood plasma. For vaccinated individuals, Abs to the SARS-CoV-2 receptor-binding domain antigen (RBDag) were determined. Statistical processing of the results was carried out using Excel 2010 and other programs. Differences were designated as statistically significant at p<0.05.

Results. The seroprevalence of the general population was 48.7% (95% CI 47.7-49.7), with a maximum in the group of '60-69 year old' (59.2% (56.6-61.7)) and a minimum in the group '1-17 y.o.' (32.7% (95 CI 29.4-36.1)). The largest proportion seropositive was found in the Chui region (51.3% (95% CI 47.9-54.8)). The lowest was in Osh city (38.1% (95 CI 32.6-43.9)). The maximum seropositivity was detected among healthcare workers (57.1% (95% CI 55.4-58.8); the minimum was noted among artists (38.6% (95% CI 26.0-52.4)). Asymptomatic SARS-CoV-2 positivity was 79.1% (96% CI 77.9-80.3). Vaccination with Sputnik V, EpiVacCorona, or Sinopharm formed comparable levels of immunity.

Conclusions. The herd immunity to SARS-CoV-2 Nag is 48.75% (95% CI 47.7-49.7), and the overall immunity (Nag + RBDag) is 57%.

Kyrgyzstan

population

coronavirus

SARS-CoV-2

COVID-19

herd immunity

seroprevalence

antibodies

N antigen

RBD antigen

vaccination

spike antigen

September 2021 marks 21 months since the moment when mankind was, unfortunately, forever divided into two eras: before and after the COVID-19 pandemic caused by the novel coronavirus (SARS-CoV-2). The so called 'Spanish' influenza pandemic (1918-1920) was a similar milestone event of the early 20th century. The influenza pandemic had a beginning and an end [1], yet the COVID-19 pandemic is ongoing. Alternating episodes featuring decreases and increases in the numbers infected are occurring, with similar dynamics being observed in most countries globally. As of September 11, 2021, 225,241,173 human SARS-CoV-2 infections were registered worldwide, which is 28.8 thousand people per 1 million population. Of those, 4,641,113 people (2%) have died [2].

The Kyrgyz Republic (Kyrgyzstan) is a Central Asian country located in the western and central areas of the Tian Shan mountain system. The population of Kyrgyzstan was 6,522,811 people as of 01.01.2020. The average population density is about 33 per km² [3]. In regional terms, the population is distributed unevenly. The bulk is concentrated in the two largest cities, Bishkek and Osh, where about 22% of the Republic's population lives. Bishkek city (the capital of the country) is home to 6371 people per km². The population density in Osh city is 2134 per km². In the rest of the Republic, there are 32 per km² [IQR: 17.4-40.6]. In the Issyk-Kul and Naryn regions, there are 12 per km² and 6 per km², respectively. Such an uneven population distribution inevitably affects infectious disease levels in the country.

As of September 12, 2021, 177,158 cases of SARS-CoV-2 infection were registered in Kyrgyzstan (19,268 per 1 million population). Of those, 2,573 people died (1.45%). COVID-19 incidence in 2020-2021 manifested itself in three waves. The first wave began in the last 10 days of June 2020 and ended by mid-August 2020. The beginning of the second wave fell on the last 10 days of September 2020, and it ended only at the end of December 2020. The third wave formed in the last 10 days of April 2021. Peak incidence was noted in mid-July, and the end fell on the end of August 2021. The incidence during these periods ranged from 500 to 1600 people per day. As of September 13, 2021, the number of newly infected people in the Republic was 92 over the previous 7 days [4]. In other words, SARS-CoV-2 epidemic process activity was not high during this period. The largest numbers of cases were registered in the cities of Bishkek and Osh, as well as in the Osh, Jalal-Abad, and Chui regions.

Vaccination of the population against COVID-19 can affect conditions in terms of morbidity. Three vaccines are used in Kyrgyzstan: Gam-COVID-Vac ('Sputnik V', Russia); EpiVacCorona (Russia); and Sinopharm (PRC). As of 09/13/2021, 219809 people (3.3%) had been vaccinated with one dose of vaccine, and 530448 people (8.1%) had been completely vaccinated [5]. Thus, only 11.4% of the Kyrgyz population is protected from COVID-19 to some extent [6]. Nevertheless, the proven efficacy of the vaccines used convincingly indicates that there is no alternative to mass vaccination in order to achieve the threshold level of herd immunity, which ranges from 60 to 85% of the population [7, 8]. A certain contribution to protection is also made by post-infectious immunity that develops as a result of transmitted COVID-19 [9-11]. Thus, the real seroprevalence level of the population consists of post-infectious and post-vaccination components of immunity.

The purpose of this study was to assess the collective SARS-CoV-2 immunity of the Kyrgyz population, formed as a result of previous infection and/or immunization. In the former, immunity features antibodies (Abs) to the nucleocapsid antigen (Nag). In the latter, immunity features Abs to the SARS-CoV-2 spike protein's receptor-binding domain antigen (RBDag). Such studies have not been previously carried out in Kyrgyzstan.

2.1 Formation and randomization of the volunteer cohort

The study was organized and carried out as part of activities under a program of scientific cooperation between countries of Eastern Europe, the Caucasus, and Central Asia in accordance with: a Rospotrebnadzor Order (dated 09.09.2021 No. 512) on "The Procedure For Implementing Orders Of The Government Of The Russian Federation" (dated 18.06.2021, No. 1658-r) on the one hand; and Order of the Minister of Health and Social Development of the Kyrgyz Republic (dated July 23, 2021 No. 839) on the other.

A cross-sectional, randomized study of SARS-CoV-2 herd immunity was carried out according to a program developed by Rospotrebnadzor, with the participation of the Saint Petersburg Pasteur Institute, taking into account WHO recommendations [12], from 28.06 to 03.07.2021. In all stages of the study (collection, organization, and analysis of data), cloud (internet) technologies were used [13].

The first step of the research was the formation of a group of volunteers and information gathering. During this period, each volunteer, or his/her legal representative, was familiarized with the goals and conditions of the upcoming trial, followed by signing of an informed consent. The study was organized in accordance with the provisions of the Declaration of Helsinki and approved by the ethics committees of the Preventive Medicine Research and Production Association (protocol No. 7, ref. No. 01-288, dated 09.12.2020) and the Saint Petersburg Pasteur Institute (protocol No. 64, dated 26.05.2020).

In accordance with the specific equation of the de Moivre Laplace theorem [14], 9,471 people were selected to participate in the study. The volunteers were randomized according to their place of residence, taking into account proportional representation of each region of the Republic (Table 1).

Table 1. Number of surveyed residents living in various regions of the Kyrgyz Republic.

Region	Population	Population density, per км²	Number analyzed	Share of the number of surveyed persons, %	Share of the total national population, % (95% CI)
Bishkek city	1 053 915	6273	2326	24.6	0.22 (0.21-0.23)*
Osh city	388 428	2134	299	3.2	0.08 (0.07-0.09)*
Osh region	1 292 153	45	1201	12.7	0.09 (0.09-0.10)*
Batken region	537 365	37	719	7.6	0.13 (0.12-0.14)
Jalal-Abad region	1 238 750	32	1591	16.9	0.13 (0.12-0.14)
Talas region	266 645	23	896	9.5	0.34 (0.31-0.36)*
Issyk-Kul region	496 050	48	817	8.6	0.16 (0.15-0.18)
Naryn region	289 621	12	797	8.4	0.28 (0.26-0.29)*
Chui region	959 884	6	816	8.6	0.09 (0.08-0.09)*
OVERALL	6 522 811	32.8	9471	100.0	0.15 (0.14-0.15)

Note: asterisks mark significant differences with the final result (p<0.0001).

In total, 0.15% (95% CI 0.14-0.15) of the overall population was selected for the cohort from regions of the Republic. The smallest share of volunteers was in the city of Osh, as well as in the Osh and Chui regions. The largest shares were from the Talas region, Naryn region, and the city of Bishkek. The cohort included 2868 men (30.3%) and 6603 women (69.7%).

In addition to regional randomization, volunteers were stratified into 7 age groups (years old): 1-17; 18-29; 30-39; 40-49; 50-59; 60-69; and 70 or more (70⁺). Taking into account the peculiarities of the maturation of immunity in children [15, 16], children in the 1-17 years old group were divided into three subgroups (years old): 1-6; 7-13; and 14-17 (Table 2).

Table 2. Age structure of the cohort of surveyed volunteers.

Age group, years		Number analyzed
1 – 17		793
	1 – 6	176
	7 – 13	312
	14 – 17	305
18 – 29		1447
30 – 39		1658
40 – 49		1681
50 – 59		1739
60 – 69		1437
70⁺		716
TOTAL		9471

Note: Hereafter, the age group '70 years and older' is designated as 70⁺.

2.2. Vaccination against SARS-CoV-2.

A history of SARS-CoV-2 vaccination with one of three vaccine preparations was noted in the questionnaire by 2,439 volunteers. Three vaccines were used In Kyrgyzstan: Gam-COVID-Vac (Sputnik V), a 2-component vector vaccine (Gamaleya Research Institute of Epidemiology and Microbiology, Russia) [17, 18]; EpiVacCorona, a peptide vaccine (State Research Center of Virology and Biotechnology VECTOR, Russia ) [19]; and BBIBP-CorV, an inactivated vaccine (Sinopharm Group Co., Ltd., Shanghai, PRC) [20, 21]. Vaccination was carried out in accordance with their instructions for use. As logically follows from their compositions: immunity following Sputnik V vaccination is mainly aimed at binding RBD [22]; the inactivated BBIBP-CorV vaccine induces Abs against all viral Ags [23]; and the EpiVacCorona vaccine induces Abs to a complex of chemically synthesized peptide immunogens and SARS-CoV-2 S protein [19].

2.3 Testing of volunteers for SARS-CoV-2 antibodies

For the study, 3 ml of blood was taken from all volunteers from the cubital vein into vacutainers containing EDTA solution. Following centrifugation, blood plasma were separated from cell components and used for quantitative determinations (Thermo Scientific Multiscan). Antibodies to SARS-CoV-2 Nag were determined by enzyme immunoassay using the "Enzyme Immunoassay Reagent Kit for Quantitative Determination of Human IgG Abs to SARS-CoV-2 N Protein (N-Cov-2-IgG PS), series 001” reagent set (Saint Petersburg Pasteur Institute, Russia). The test system was calibrated in accordance with the international standard for measuring ABS against SARS-CoV-2 - Antibody Binding Units (1BAU = 5.9 unit/ml). Vaccinated volunteers were qualitatively analyzed for the presence of anti-RBD Abs using the "SARS-CoV-2 IgG ELISA screen" (LabPack, Russia) reagent set for determination in human serum and plasma. For those vaccinated with EpiVacCorona, Abs were determined using the “SARS-CoV-2 IgG Vector” enzyme immunoassay reagent set (State Research Center of Virology and Biotechnology VECTOR, Russia).

2.4 Statistical analysis

Data processing was performed using the statistics functions in Excel 2010. Confidence intervals (95% CI) were calculated by the method of A. Wald and J. Wolfowitz [24], with correction as described by A. Agresti and B. A. Coull [25]. Correlation analysis was performed according to Spearman's method. The statistical significance of differences were calculated by the z-test using the appropriate online calculator [27]. Distribution normality was checked using the Kolmogorov-Smirnov test in the Excel 2010 package. Unless otherwise indicated, differences were designated as significant when p ≤0.05.

3.1 Distribution of anti-Nag Abs among volunteers, by age

Twenty one months after the onset of the pandemic, the proportion of volunteers with Abs to SARS-CoV-2 Nag was 48.7% (95% CI 47.7-49.7). Unlike other regional countries [28, 29, 30, 31], higher seroprevalence in the age group 1-17 years old, or its subgroups, was not seen in the Kyrgyz Republic (Table 3). On the contrary, the proportion of seropositive individuals in these groups was significantly less than the cohort average (32.7% (95% CI 29.4-36.1) p<0.001)). The maximum levels of seroprevalence were recorded among volunteers in the older age groups: 50-59; 60-69; and 70⁺ years old (Table 3). The differences from the population mean were statistically significant (p<0.001).

Interesting results were obtained when quantifying anti-Nag Ab levels (Fig. 1, Table 1S).

Table 3. SARS-CoV-2 seroprevalence in different age groups of Kyrgyz residents, July 2021.

Age group, years		Number analyzed	IgG antibodies present	Seroprevalence, % (95% CI)
1 – 17		793	259	32.7 (29.4-36.1)*
	1 – 6	176	46	26.1 (19.8-33.3)
	7 – 13	312	111	35.6 (30.3-41.2)
	14 – 17	305	102	33.4 (28.2-39.0)
18 – 29		1447	539	37.2 (34.8-39.8)*
30 – 39		1658	682	41.1 (38.8-43.6)*
40 – 49		1681	852	50.7 (48.3-53.1)
50 – 59		1739	1028	59.1 (56.8-61.4)*
60 – 69		1437	850	59.2 (56.6-61.7)*
70⁺		716	399	55.7 (52.0-59.4)*
OVERALL		9471	4609	48.7 (47.7-49.7)

Note: *statistically significant differences with the mean cohort seroprevalence (overall row) (p<0.0001).

Volunteers in the first serogroup with minimal Ab levels (100-170 U/ml) were relatively evenly distributed among all age groups. There was some predominance in two groups (30-39, 40-49 y.o.) and significantly less among children 1-17 years old (p<0.0001). The trend line is shown in blue. The age distribution of seroprevalence was described by a second order polynomial equation of the form: y = -0.4143x² + 3.8929x + 5.3, with R² = 0.9482. The angle coefficient (tgα) was 0.70, which indicates a weak dependence of Ab level on volunteer age.

In the second serogroup (171-750 U/ml), the dependence was more complex. The smallest proportion of seropositive individuals was noted in the groups '1-17 years old' and '18-29 years old'; starting from 60-69 years, the trend showed a slight decrease (all differences insignificant). Such dynamics are described by the third order polynomial equation of the form: y = -0.3778x³ + 4.0798x² - 9.5782x + 22.229, with R² = 0.9414. With further increasing Ab levels in the three remaining serogroups, the tendency was still preserved, but age differences gradually smoothed out, manifesting as a simplification of the curve's shape.

In the third serogroup (751-1500 U/ml), the curve was described by the 3rd order polynomial equation: y = -0.1167x³ + 1.4976x² - 4.7786x + 8.6714, with R² = 0.9, while tgα decreased to 0.94.

Starting from the fourth serogroup group (1500-3000 U/ml), the polynomial dependence degenerated into a linear form: y = 0.7x + 0.2429, with R² = 0.97, while tgα decreased to 0.68. The dependence of Ab level on age was still preserved, but its magnitude decreased.

Finally, in the 5th serogroup (>3000 U/ml), the age dynamics of antibodies fully corresponded to the upward linear equation of the form: y = 0.35x + 1.3, with R² = 0.87, while tgα decreased to 0.40. There were no statistically significant differences between Ab levels among volunteers of any age in this serogroup.

Thus, the age distribution of the percent seropositive individuals within one serological interval confirmed: lower Ab levels among young and middle-aged individuals; and a statistically significant increase among older volunteers. This relationship between age and anti-Nag Ab level can be considered a feature of SARS-CoV-2, and it has been established in other studies [32, 33].

3.2 Regional distribution of SARS-CoV-2 seropositivity

In Kyrgyz regions, the proportion of seropositive volunteers varied from 38.1% (95% CI 32.6-43.9) in the Osh region to 53.3% (95% CI 49.8-56.8) in the Naryn region (Table 4). The differences are statistically significant (p<0.0001).

Table 4. SARS-CoV-2 seroprevalence among residents of different Kyrgyz regions.

Region	Surveyed volunteers			Morbidity, ‱0
Region	Total	Seropositive	Seroprevalence, % (95% CI)	Morbidity, ‱0
1. Bishkek city	2326	1019	43.7 (41.8-45.8)*	4846.8
2. Osh city	299	114	38.1 (32.6-43.9)*	2632.2
3. Osh region	1201	639	53.3 (50.3-56.1)*	773.5
4. Batken region	719	325	45.1 (41.5-48.9)	954.5
5. Jalal-Abad region	1598	792	49.7 (47.1-52.0)	1516.4
6. Talas region	898	445	49.5 (46.2-52.9)	1103.3
7. Issyk-Kul region	817	431	52.8 (49.3-56.2)	2099.9
8. Naryn region	797	425	53.3 (49.8-56.8)*	1928.1
9. Chui region	816	419	51.3 (47.9-54.8)	1057.5
TOTAL	9471	4609	48.7 (47.7-49.7)	1926.8

*Statistically significant differences with the cohort mean seroprevalence (p<0.0001).

Unfortunately, we were unable to identify correlations between population density, seroprevalence, and morbidity. To a certain extent, this is probably due to the very uneven distribution of the population over the Republic's regions. About 20% of the total population is concentrated in the two largest cities (Bishkek, Osh); only 8.3 to 8.6% live in the Issyk-Kul, Naryn, or Chui regions (Table 1). Such a significant range in numbers suggests that in most of the country, morbidity and seroprevalence dynamics mainly develop in a random manner, without forming patterns.

3.3 SARS-CoV-2 seroprevalence in volunteers from different professional groups

To analyze the role of risk factors, the proportion of seropositive volunteers in different social and professional groups was assessed (Table 5). The highest seroprevalence level, significantly higher than the average for the surveyed population, was found in the medical worker group (57.1% (95% CI 55.4-58.8) p<0.0001). The lowest seroprevalence was observed in artists and office workers (p<0.001).

Table 5. SARS-CoV-2 seroprevalence among volunteers from different professional groups.

Professional category	Volunteers analyzed		Seroprevalence % (95% CI)
Professional category	Total	Seropositive	Seroprevalence % (95% CI)
Medicine	3301	1885	57.1 (55.4-58.8)*
Science	52	22	42.3 (28.7-56.8)
Business	330	141	42.7 (37.3-48.3)*
Education	628	282	44.9 (41.0-48.9)
The Arts	57	22	38.6 (26.0-52.4)
Manufacturing	168	69	41.1 (33.6-48.9)*
Transportation	93	39	41.9 (31.8-52.6)
Armed services	106	51	48.1 (38.3-58.0)
Government service	898	464	51.7 (48.4-55.0)
Office work	433	170	39.3 (34.6-44.0)*
Unemployed	938	395	42.1 (38.9-45.3)*
Other	464	202	43.5 (39.0-48.2)*
TOTAL	7468	3742	50.1 (49.0-51.2)

*Statistically significant differences with the mean seroprevalence among volunteers of working age (p<0.0001).

Significantly lower seroprevalence values were noted in business workers, those in manufacturing, the unemployed, and in persons in the classification 'Other' (all differences statistically significant, p<0.05). The results obtained are in good agreement with data from similar studies. In a significant number of publications, increased seroprevalence was especially often noted in medical workers who have frequent contact with COVID-19 patients [34, 35, 36].

3.4 Seroprevalence in COVID-19 convalescents and those in contact with them

Among those who experienced manifest COVID-19, the proportion seropositive was 64.5% (95% CI 61.9-67.1) (Table 6). As expected, this indicator was significantly higher than the surveyed cohort average (48.7% (95% CI 47.7-49.7) p<0.0001).

Table 6. Seroprevalence in COVID-19 convalescents and contacts.

Group

Number analyzed

Presence of anti-Nag IgG Abs (n)

Seroprevalence,

% (95% CI)

convalescents

1320

852

64.5 (61.9-67.1)

contacts

2212

1099

49.7 (47.6-51.8)

Note: convalescents - volunteers who indicated recovered COVID-19 in the questionnaire; contacts - persons who indicated (questionnaire) contact with a patient or COVID-19 convalescent.

The seroprevalence among those who noted transmitted COVID-19 in the questionnaire was significant, but still not as high as one might expect. There are at least three explanations for this situation. Firstly, the data on transmitted infection are self-reported, as obtained from the questionnaire completed by the volunteer only. Secondly, transmitted infection does not always leave a trace in the form of detectable anti-Nag Ab levels. It is believed that about 35% of COVID-19 survivors produce Abs at concentrations below the minimum threshold of detection [37]. Thirdly and finally, there is a certain period of Ab circulation after which concentrations decrease below methodological sensitivity thresholds. According to some reports, SARS-CoV-2 specific Ab levels begin to decline in the blood 2-3 months post infection [38].

The role of convalescents is not limited only to their contribution to the level of population immunity. They play an essential role in infectious spread and continuation of the epidemic process. In the clinical and post-clinical phases, patients are able to transmit the pathogen to others via emission of virus in particles of saliva when coughing, sneezing, or talking. Among the surveyed volunteers, 2,212 people indicated the presence of such contacts by questionnaire. The seroprevalence level in these individuals was 49.7% (95% CI 47.6-51.8) (Table 6). By comparing these data with the average cohort seroprevalence value, it can be concluded that the contribution of contacts to the general level of SARS-CoV-2 herd immunity is insignificant. This is probably due to the low population density in most regions of the Republic.

3.5 Assessment of the proportions of asymptomatic COVID-19 among seropositive volunteers

A characteristic feature of SARS-CoV-2 is a high proportion of asymptomatic forms of infection [39]. In this study, individuals were classified as asymptomatic who, in addition to Abs to Nag, did not show any symptoms of COVID-19. According to our data, their share can reach 90% or more of all seropositive individuals [28, 30, 40]. This study identified 3647 asymptomatic cases in 4609 seropositive volunteers (79.1% (95% CI 77.9-80.3)) (Table 7).

Table 7. Share of asymptomatic infections, relative to overall seropositive volunteers, by age group.

Age group, years	Number seropositive		Asymptomatic share % (95% CI)
Age group, years	Total	Asymptomatic	Asymptomatic share % (95% CI)
1 – 17	259	234	90.3 (86.1-93.7)*
18 – 29	539	452	83.9 (80.5-86.9)*
30 – 39	682	557	81.7 (78.6-84.5)
40 – 49	852	680	79.8 (77.0-82.5)
50 – 59	1028	781	76.0 (73.2-78.6)
60 – 69	850	639	75.2 (72.1-78.1)
70⁺	399	304	76.2 (71.7-80.3)
TOTAL	4609	3647	79.1 (77.9-80.3)

Note: *Statistically significant differences with the mean seroprevalence value in the cohort.

The largest number of asymptomatic, yet SARS-CoV-2 seropositive, individuals was found among volunteers aged 1-17 and 19-29 years (p<0.0001). In the remaining groups, the number of such individuals was relatively homogeneous. There were no statistically significant differences, in comparison with the average population, in these groups. In general, the level of such individuals (asymptomatic seropositive) is close to that of Russia, another Eurasian country [30].

3.6 Evaluation of seroprevalence in vaccinated volunteers

Vaccination was noted in the questionnaire by 2,439 volunteers. Since plasma samples from 44 surveyed were invalid, further analysis took into account data on 2395 plasma samples from vaccinated volunteers (Tables 8-11). In general, immunity to RBDag, which we called post-vaccination immunity, was observed in 91.0% (95% CI 89.2-92.1) of those vaccinated. There were no statistically significant differences depending on vaccine type. In 7.8% (95% CI 6.8-9.0) of vaccinated volunteers, neither post-infectious immunity (Abs to Nag), nor post-vaccination immunity (Abs to RBDag), were detected.

Table 8. Presence of IgG Abs to SARS-CoV-2 Ags in volunteers immunized with the Sputnik V vaccine (393 people).

		IgG Abs to Nag
		positive (n=180)	negative (n=213)
IgG Abs to RBD	positive(n=356)	173	183
IgG Abs to RBD	negative (n=37)	7	30

Table 9. Presence of IgG Abs to SARS-CoV-2 Ags in volunteers vaccinated with the EpiVacCorona vaccine (133 people).

		IgG Abs to Nag
		positive (n=83)	negative (n=50)
IgG Abs detected by the Vector test system	positive (n=110)	82	28
IgG Abs detected by the Vector test system	negative (n=23)	1	22

Table 10. Presence of IgG Abs to SARS-CoV-2 Ags in volunteers vaccinated with the Sinopharm vaccine (1869 people).

		IgG Abs to Nag
		positive (n=1158)	negative (n=711)
IgG Abs to RBD	positive (n=1713)	1137	576
IgG Abs to RBD	Negative (n=156)	21	135

Table 11. Seroprevalence in vaccinated volunteers.

Vaccine	Post-infectious immunity (IgG Abs to Nag)		Post-vaccination immunity (IgG Abs to RBD)		Immunity is negative*
Vaccine	n	% (95% CI)	n	% (95% CI)	n	% (95% CI)
Sinopharm	1158	62.0 (59.7-64.1)**	1713	91.6 (90.3-92.8)	135	7.2 (6.1-8.5)
Sputnik V	180	45.8 (40.8-50.9)	356	90.6 (87.3-93.3)	30	7.6 (5.2-10.7)
EpiVacCorona	83	62.4 (53.6-70.7)**	110	82.7 (75.2-88.7)	22	16.5 (10.7-24.0)
OVERALL	1421	59.3 (57.4-61.3)	2179	91.0 (89.8-92.1)	187	7.8 (6.8-9.0)

Note: *There is neither post-infectious nor post-vaccination immunity. **The presence of Abs to Nag in persons vaccinated with Sinopharm or EpiVacCorona cannot be unambiguously regarded as a result of previous infection.

Analysis of data obtained from volunteers vaccinated with Sputnik V (Table 8) showed that 180 people (45.8% (95% CI 40.8-50.9)) likely had evidence of SARS-CoV-2 infection; these were likely asymptomatic, as vaccination was given to those without a COVID-19 diagnosis. In these individuals, the response to vaccination was more pronounced: 173 seropositive out of 180 patients (96.1% (95% CI 92.2-98.4)). Among those not previously infected, there were 183 seropositive out of 213 (85.9% (95% CI 80.5-90.3)).

The results obtained for volunteers vaccinated with the EpiVacCorona vaccine (Table 9) showed that post-vaccination immunity was developed in at least 82.7% (95% CI 75.2-88.7%). In addition, 62.4% (95% CI 53.6-70.7) of the volunteers had anti-Nag Abs, which could be a consequence of either previous infection or vaccination. If we take the figure of 45.8% calculated for the Sputnik vaccine as the average proportion of those who had recovered (asymptomatic), then approximately 16.6% of the volunteers acquired anti-Nag Abs as a result of vaccination.

Analysis of the data obtained for those vaccinated with Sinopharm (Table 10) showed that at least 91.6% (95% CI 90.3-92.8) of volunteers acquired post-vaccination immunity. Perhaps this figure is higher since the 21 people who were not found to have anti-RBD Abs had anti-Nag Abs; these could be due to either previous infection or vaccination. Based on the data obtained, it is possible to calculate the total contribution of vaccines to population immunity (Table 12).

Table 12. Vaccine contributions to herd immunity of the surveyed volunteers.

Vaccine	Abs to RBD Sag		*Abs to Nag
Vaccine	share, %	contribution	share, %	contribution
Sputnik V	74.1	1.9	(does not induce)
EpiVacCorona	25.4	0.3	74.5	0.9
Sinopharm	33.6	6.1	66.4	12.0
Total contribution	-	8.3	-	12.9

Note: *Post-vaccination anti-Nag immunity is not cumulative since it has already been taken into account in the level of post-infectious population immunity, which was 48.7% (95% CI 47.7-49.7).

Thus, an additional contribution of vaccines to population immunity was made only by Abs to SARS-CoV-2 RBD, the total contribution of which was 8.3%. In total, the final determination of population immunity was: 48.7 + 8.3 = 57%.

Based on the available official data, the incidence in the Republic can be regarded as consistently low. In the global ranking of countries, in terms of the number of infected, Kyrgyzstan occupies 92nd place. The total number of infected people was 177,784 people (2,725 per 100,000 residents) as of September 16, 2021. In the last week of September 2021, the number of infections registered daily did not exceed 100 (0.015 ‰). More than 96.7% of those infected had recovered as of September 16. Over the entire pandemic period, 1.4% of those officially diagnosed died. Such favorable data is probably a consequence of low population density not exceeding 33 per km². In a number of areas, such as the Chui region, it is as low as approximately 6 per km².

Unlike a number of Russian regions [28, 29, 30], the age structure of seroprevalence was characterized by significantly higher indicators among persons in older groups (50 years and above) (Table 3). The differences were statistically significant at p<0.0001. When quantifying anti-Nag Abs, it was shown that minimal Ab levels (100-750 U/ml) prevailed among volunteers in the age groups 1-17 and 18-29 years old; maximum levels (751-3000⁺ U/ml) were found among persons aged 50 to 70⁺ years (Fig. 1, Table 1S). When analyzing any association between share of seropositive persons and areas of the Republic, no connection with region of residence was noted (Fig. 2).

In the capital of the Republic, Bishkek, the proportion seropositive was 43.7% (95% CI 41.8-45.8). It was somewhat less in the city of Osh, 38.1% (95% CI 32.6-43.9). In contrast, the highest shares of seropositive volunteers were found in regions with the lowest population densities: the Naryn region with 53.3% seropositive (95% CI 49.8-56.8); and the Chui region with 51.3% seropositive (95% CI 47.9-54.8). Naturally, with such a distribution, it was not possible to reveal any correlation dependencies for pairs: seropositivity with population density; morbidity with seropositivity; or morbidity with population density.

When assessing the influence of occupational factors on seroprevalence, the largest proportion of seropositive individuals was found among medical workers. This result was expected since doctors are most often in contact with COVID-19 patients. It is no coincidence that medical personnel, especially those who work in infectious disease departments and hospitals, are classified as at risk regarding nosocomial SARS-CoV-2 infection frequency [41,42]. The smallest shares of seropositive persons were noted among creative workers and office workers (Table 6).

The share of asymptomatic SARS-CoV-2 among seropositive volunteers was 79.1% (95% CI 77.9-80.3), with a significant predominance of such forms among children 1-17 years old (90.3% (95% CI 86.1-93.7) p<0.0001). This is significantly lower than in other countries, for example, in Russia [28, 43, 44]. SARS-CoV-2 vaccination deployed in Kyrgyzstan has contributed to an increase in anti-RBD Ab levels by 8.3%. In result, the overall level of population immunity has reached 57%; this is still significantly below the required level for herd immunity and creates risks of a further increase in COVID-19 incidence.

The collective immunity to SARS-CoV-2 Nc, excluding the contribution of post-vaccination anti-RBD immunity, was 48.75 (95% CI 47.7-49.7). The total, taking into account immunization with all vaccines, was 57%. The largest share of seropositive persons was noted among volunteers aged 50-70⁺ years. Statistically significant regional differences were noted in the Republic. Specifically, seroprevalence was significantly lower in Osh city, and significantly higher in the Naryn region, than the national average (p<0.0001).

The highest level of seroprevalence, detected in the medical worker group (57.1% (95% 55.4-58.8)), significantly exceeded the national average (50.1% (95% CI 49.0-51.2) p<0.0001). The share of asymptomatic individuals among those who were seropositive was 79.1% (95% CI 77.9-80.3). Maximums were observed in children (90.3% (95% CI 86.1-93.7)) and young people 18-29 years old (83.9% (95% CI 80.5-86.9)). The differences were statistically significant at p<0.0001.

Comprehensive analysis shows a satisfactory level of collective SARS-CoV-2 immunity in the Kyrgyz population in the context of a relatively low COVID-19 incidence. Mass vaccination deployed in the Republic has certainly benefited the overall situation. Nevertheless, the pace of this process is still insufficient, which represents a risk of increased COVID-19 incidence.

Abs antibodies

Ags antigens

CI confidence interval

COVID-19 coronavirus disease 2019

ELISA enzyme-linked immunosorbent assay

Ig immunoglobulin

IQR interquartile range

Nag nucleocapsid antigen

R²determination coefficient

RBD receptor binding domain

RBDag receptor binding domain antigen

SARS-CoV-2 severe acute respiratory syndrome coronavirus 2

Sag spike protein antigen

tgα angle coefficient

WHО World Health Organization

Ethic declaration

The study was organized in accordance with the provisions of the Declaration of Helsinki and approved by the ethics committees of the Preventive Medicine Research and Production Association (protocol No. 7, ref. No. 01-288, dated 09.12.2020) and the Saint Petersburg Pasteur Institute (protocol No. 64, dated 26.05.2020).

Consent to publication

not applicable

Data Availability

All results are presented in the tables. The data for Figure 1 are presented in Supplementary Materials Table S1.

Conflict of Interests

The authors declare that they have no competing interests.

Financing.

The financing of the program was carried out at the expense of the state budgets of Kyrgyzstan and the Russian Federation. The authors declare no sponsorship funding

Acknowledgments

The authors express their sincere gratitude to Edward S. Ramsay for valuable help (translation, editing) with preparation of this article.

Author Contributions

AYP, OTK, VYS - general planning and coordination of work at the intergovernmental level; SAE - research organization; ZSN, GSS, JNN, AAD, GZS - collection and primary processing of information; AMM, EVZ, VGD, IVK, OBZ, ARR - sample preparation and immunological analysis of blood samples; VNV, VAI - preparation and control of diagnostic systems; IVL - software; VSS - statistical analysis, writing and final verification of the article text; AAT - general research guidance, article editing. All authors have read and approved the final manuscript.

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No competing interests reported.

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SARS-CoV-2 Herd Immunity of the Kyrgyz Population in 2021

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