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0SEROTYPE SPECTRUM AND EFFECTIVENESS OF VACCINE PROPHYLAXIS AGAINST S.PNEUMONIAE IN CHILDREN
A.Shamansurova
Tashkent pediatric medical institute https://doi.org/10.5281/zenodo.10849733
Abstract. In order to assess the effect of vaccination against Streptococcus pneumoniae on the serotype spectrum of pneumococcus, we conducted a bacteriological study of nasopharyngeal mucus of 247 healthy children attending kindergarten. In 35.6% (20) of practically healthy children, S. pneumoniae was isolated and serotyping of the isolated samples was carried out. In order to assess the effect of vaccination against Streptococcus pneumoniae on the serotype spectrum of pneumococcus, we conducted a bacteriological study of nasopharyngeal mucus of 247 healthy children attending kindergarten. In 35.6% (20) of practically healthy children, S. pneumoniae was isolated and serotyping of the isolated samples was carried out. The most common pneumococcal serotypes were 15A/F, 6 A/B, 9 A/V and 9 F, followed by 5 and 7 A in frequency /F, 23F serotypes. A study of specific antibodies to pneumococcus in vaccinated children showed a high level of immune response. Thus, it was found that vaccination with commercial pneumococcal vaccines protects the majority of vaccinated children. To assess the effectiveness of vaccination, it is necessary to study the circulation of serotypes in children after vaccination.
Keywords: vaccination, S.pneumoniae, serotypes, immune response.
Relevance. The problem of diagnosis and treatment of pneumococcal diseases continues to be one of the most pressing in modern healthcare. The most effective and cost-effective method of preventing pneumococcal infection is vaccination. According to WHO, "...vaccination is the only way to significantly influence the incidence of pneumococcal infection" [6]. Therefore, it is necessary to develop and implement measures to prevent these diseases in children. According to the WHO position, "...in many countries, the routine use of pneumococcal conjugate vaccines has sharply reduced the number of cases of serious diseases caused by this microorganism," including pneumonia" [11,12]. Considering the serotype diversity of pneumococcus, it is especially important to study circulating pathogenic strains of Streptococcus pneumoniae. To assess the effectiveness of vaccination, the study of the effect of vaccination against Streptococcus pneumoniae on the incidence of respiratory diseases in children, as well as the serotype spectrum of pneumococcus in young children deserves the greatest attention [4,5,7].
In world practice, special attention is paid to research into the modern serotype landscape of pneumococci [9]. Mass vaccination with pneumococcal vaccines over several years has sharply reduced the incidence of invasive pneumococcal infections associated with vaccine strains of pneumococcus [10]. However, the spectrum of circulating Streptococcus pneumoniae serotypes may vary between countries, so regional data on the most relevant pneumococcal serotypes are required to develop new vaccines and study their epidemiological effectiveness. In this regard, studying the serotype landscape after the introduction of the vaccine, as well as assessing the impact of vaccination on morbidity, is extremely relevant.
In Uzbekistan, isolated work has been carried out on the diagnosis and treatment of pneumococcal infections in children [1]. The authors determined the spectrum of circulating
pneumococcal serotypes before the introduction of the vaccine against Streptococcus pneumoniae. However, to assess the effectiveness of vaccination, data are needed on the incidence, as well as on the serotype spectrum of pneumococcus after inclusion of vaccination in the preventive vaccination schedule. Data on the incidence and serotype landscape of pneumococcal infections can be considered as a criterion for predicting the effectiveness of national vaccination programs [2,8].
In accordance with the calendar of preventive vaccinations of the Republic of Uzbekistan, vaccination is carried out routinely for children at the age of 2, 3 months with a minimum interval of 4 weeks and a booster dose at 12 months (Table 1).
Table 1
Children's vaccination schedule
Age at which vaccination began Dose Dose Number Scheme
From 2 to 6 months. 0.5 ml 2+1 revaccination 2+1 revaccination 2+1 : two doses with an interval of at least 4 weeks between administrations. The first dose was administered at 2 months of life, the second - from 3 months of life. Revaccination was carried out once every 12 months.
The study of carriage of Streptococcus pneumoniae is especially relevant, because carriage of pneumococcus leads to the spread of pneumococcal diseases in contact children. The study of the serotype spectrum of Streptococcus pneumoniae after the introduction of vaccination remains poorly studied.
In order to assess the effect of vaccination against Streptococcus pneumoniae on the serotype spectrum of pneumococcus, we conducted a bacteriological study of nasopharyngeal mucus of 247 healthy children attending kindergarten. In 35.6% (20) of practically healthy children, S. pneumoniae was isolated and serotyping of the isolated samples was carried out (Table 2). A prospective study was conducted using general clinical, bacteriological, and serological research methods.
Table 2.
Pneumococcal serotypes isolated from healthy children.
Serotypes abs. %
2 5 3,2
3 3 1,9
5 11 7,1
6A/B 16 10,4
7A/F 11 7,1
9A/V 15 9,7
9L/N 8 5,2
11A/D 1 0,6
12A/B/F /44/46 2 1,3
14 13 8,4
15A/F 19 12,3
16A/F 4 2,6
17A/F 2 1,3
18A/F 1 0,6
19A 6 3,9
19F 14 9,1
22A/F 4 2,6
23F 9 5,8
23A 7 4,5
33A/F/37 3 1,9
Total 154 100
Determination of the serotype of S.pneumoniae cultures showed that the most common pneumococcal serotypes were 15A/F, 6 A/B, 9 A/V and 9 F, followed by serotypes 5 and 7 A/F, 23F.
To assess the effectiveness of vaccination, it is also important to know the level of specific antibodies to each polysaccharide component of the vaccine in blood serum. The seroconversion rate is an indicator of the immune response.
The WHO expert working group identified the seroconversion rate as an immunological correlate of effectiveness, i.e. the proportion of individuals with a level of type-specific IgG antibodies in a concentration higher than 0.35 p,g/ml of vaccination [11, 12].
In order to assess the humoral immune response to pneumococcus, we tested the blood of children who received 3-fold vaccination (2+1) with Prevenar-13 or a 10-valent vaccine for the presence of type-specific IgG antibodies. The study was conducted in children who were hospitalized with a diagnosis of community-acquired pneumonia (26 children), of which 11 children received the vaccine before 2020 (Prevenar -13) and 15 children received the 10-valence vaccine Pneumosil (India) (10BB). As a control group, the blood sera of 12 children without pneumonia were studied (children who were in the hospital for various surgical conditions (forearm dislocation, nasal injury, calculous cholecystitis, etc.).
Research results. To assess immunological effectiveness, we determined specific anti-SPP IgG antibodies to capsular polysaccharides of Streptococcus pneumoniae using ELISA in immunized children no earlier than 2 months after the last administration of vaccines. There were 11 children who received Prevenar-13 and 15 children who received the 10-valent vaccine. The sera of children who did not receive pneumococcal vaccination (12 children) were studied as a control group.
When analyzing the sera of children with CAP (n=11) vaccinated with a 13-valent vaccine (Table 1), it was found that the level of specific antibodies to individual CPS in them ranged from 35 c.u. e. to KPS Pn-9N up to 101 cu. e. to KPS Pn-23F.
At the same time, the average lower limit for most CPS was 30 - 40 USD. units, and the top one is about 60-100 cu. units Calculation of the average antibody level showed that for most CPS it was at the level of 40-50 c.u. units (p<0.05). At the same time, for KPS Pn-23F was more than 100 cu. units, which is associated with the presence of individuals with a high level of antibodies (AT) to it. The studies showed that all children in the control group (11 children) had a diagnostically significant level of IgG to one or simultaneously several CPS. When analyzing the
sera of children vaccinated with the 10-valent vaccine, it was found that the level of specific antibodies to individual CPS was in a lower range of values (30 - 40 units) than in those vaccinated with Prevenar-13.
Table 3.
Immunological effectiveness of vaccination against pneumococcal infection in children
Serotype Level of specific antibodies in children with
CAP (a.u.)
Prevenar-13 Pneumosil
Pn1 67,4±22,6 40,6±8,3
Pn 3 41,3±6,4 33,2±3,8*
Pn 4 44,2±6,4 42,2±4,2
Pn 5 53,9±10,9 46,7±5,3*
Pn 6A 41,4±7,9 33,2±3,0
Pn 6B 41,7±5,8 40,2±4,1
Pn 7F 38,8±6,7* 42,4±7,2
Pn 9N 35,1±4,5 37,1±5,6
Pn 9 V 47,0±6,9 49,9±7,9
Pn 14 53,4±9,4 49,4±6,9*
Pn 15B 44,8±6,9* 36,3±4,3*
Pn 18C 63,0±26,3* 30,5±2,6*
Pn 19A 50,1±6,6 62,7±17,8*
Pn 19F 59,1±14,8 42,1±3,9*
Pn 23F 101,0±29,3* 54,1±11,9
Note: (*- P<0.05); - reliability of data in relation to the group of vaccinated children until 2020
It was found that after vaccination with Prevenar -13, the level of IgG to CPS Pn-1, Pn-18C most often increased and the level of antibodies to Pn-23 increased significantly (2 times), which probably indicates a higher immunogenicity of these CPS in Prevenar -13. The weakest increase was in the level of antibodies to the SIJ PN-3, 4, 6A, 6B, 7F, 9N, 9V, 14, 15B. Children vaccinated with the 10-valent vaccine had levels of antibodies to 70% CPS (Pn 1, 3, 4, 6A, 6B, 7F, 9N, 9V, 14, 15B) significantly lower than those vaccinated with Prevenar-13. It should be noted that in those vaccinated with the 10-valent vaccine, antibody levels to only two CPS (Pn 19A and 7F) increased significantly.
When analyzing the sera (n=12) of the control group of children without pneumonia, the following results were obtained (Table 4).
Table 4.
Level of IgG to individual capsular polysaccharides of S.pneumoniae and vaccines Prevenar-13 and Pneumosil in vaccinated and unvaccinated children (a.u.)
Serotype Control group Main group Prevenar-13 Pneumosil
Pn1 53,2±9,7 67,4±22,6 40,6±8,3A
Pn 3 54,9±13,9 41,3±6,4 33,2±3,8*A
Pn 4 56,4±16,5 44,2±6,4 42,2±4,2
Pn 5 60,5±16,3 53,9±10,9 46,7±5,3*
Pn 6A 41,8±8,6 41,4±7,9 33,2±3,0A
Pn 6B 46,9±11,4 41,7±5,8 40,2±4,1
Pn 7F 41,7±10,1 38,8±6,7* 42,4±7,2
Pn 9N 43,7±10,1 35,1±4,5 37,1±5,6
Pn 9V 49,8±12,6 47,0±6,9 49,9±7,9
Pn 14 58,5±10,4 53,4±9,4 49,4±6,9*A
Pn 15B 63,1±8,4 44,8±6,9* 36,3±4,3*A
Pn 18C 45,8±10,9 63,0±26,3* 30,5±2,6*A
Pn 19A 55,6±14,7 50,1±6,6 62,7±17,8*
Pn 19F 61,9±18,7 59,1±14,8 42,1±3,9*A
Pn 23F 55,9±11,8 101,0±29,3* 54,1±11,9A
Note: * - reliability of data in relation to the control group (* - P <0.05); A- reliability of the data in relation to the group of vaccinated children until 2020 (A- P <0.05).
In the control group of children (who did not receive vaccination) for Pn1, the average AT level was 53.2 c.u. (p <0.05) (Table 4). However, the average values for CPS Pn-3, Pn-14, Pn-7F, Pn-5, Pn-15B and Pn-19F in unvaccinated children were 1.3-1.5 times higher. For other CPS (Pn-6A, Pn-6B, Pn-9N, Pn-4, Pn-9V) the difference was not significant. In addition to those described, an analysis was carried out of the frequency of increases in the level of antibodies to each CPS in the post-vaccination period.
The level of specific antibodies in these children slightly exceeded the range of values in individuals of the first two groups. The peculiarity was that the lower limit of AT level values for most CPS was higher and amounted to about 40-60 cu. e. The average values for all CPS were at the level of 41-63 c.u. These data, in our opinion, indicate that unvaccinated children in this group have already repeatedly encountered pneumococcal infection. The maximum increase in the average level of specific IgG (1.7 times) was observed only for CPS Pn-19F, and the minimum -for CPS Pn-9N. It should be noted that the Prevenar-13 vaccine does not contain Pn-9N CPS, which is probably why an increase in the level of antibodies to this polysaccharide was not observed in children who received the vaccine. Thus, analysis of the same sera showed a higher level of IgG in the post-vaccination period for the Prevenar-13 vaccine to a greater extent than for the 10-valent vaccine (1.3-2 times).
Conclusion. The predominant serotypes in the isolated S.pneumoniae strains were serotypes 1, 5 and 6A. Further in frequency were 2, 3, 4, 6 V, 19F.
When examining blood sera for specific antibodies, it was shown that the highest level of IgG to 15 CPS of pneumococcus in the pre-vaccination period was demonstrated by the sera of children in the control group. In second place in terms of the level of antibodies to KPS pneumococcus were the sera of children who received Prevenar-13, and in third place were the blood sera of children vaccinated with the 10-valent vaccine (Table 4).
In those vaccinated with Prevenar-13, the highest level of antibodies was observed to KPS 23F (more than 100 units), the lowest to KPS serotypes absent in the 13-valent vaccine (9N, 15B). As noted above, children who received the 10-valent vaccine had antibody levels significantly lower than those of the previous group. This can be explained by the greater effectiveness of the 13-valent vaccine. The relatively low level of antibodies in children with CAP compared with a control group of children without pneumonia suggests that vaccination with commercial pneumococcal vaccines in children with possibly altered immune status or suffering from bronchopulmonary diseases often does not lead to an increase in the level of specific antibodies to
all CPS included in the vaccine. However, high levels of antibodies were detected for some serotypes (19A, 23F). Children in the control group demonstrated a high level of specific antibodies; this fact can be explained by the absence of diseases in them that lead to an immunodeficiency state and, as a result, to a good immune response possibly altered immune status or suffering from bronchopulmonary diseases often does not lead to an increase in the level of specific antibodies to all CPS included in the vaccine. However, high levels of antibodies were detected for some serotypes (19A, 23F). Children in the control group demonstrated a high level of specific antibodies; this fact can be explained by the absence of diseases in them that lead to an immunodeficiency state and, as a result, to a good immune response. It can be assumed that some of these individuals had previously suffered from pneumococcal infection. Polyclonal activation of the immune response by some other agent is also possible. The most important, in our opinion, result of these studies was the statement of the fact that after immunization with pneumococcal vaccines, a protective level of antibodies was noted in the sera of many examined children.
Thus, it has been established that vaccination with commercial pneumococcal vaccines protects the majority of vaccinated children. To assess the effectiveness of vaccination, it is necessary to study the circulation of serotypes in children after vaccination.
REFERENCES
1. Daminov T.A., Tadzhieva N.U., Tuychiev L.N. Results of a study of S. Pneumoniae serotypes isolated from sick children with pneumococcal infection // Infection, immunity and pharmacology. - Tashkent, 2017. - special. release. Part 2. - pp. 50-55.
2. Daminov T.A., Tuychiev L.N., Tadzhieva N.U., Otamuratova N.Kh. The effectiveness of vaccination against pneumococcal infection in Uzbekistan: preliminary assessment and forecast. - Children's infections, 2018, 17(4): 34-37.
3. Instructions for use of the Prevenar 13 vaccine. LP-000798-041016. [Instruktsiya po primeneniyu vaktsiny Prevenar 13. LP-000798-041016. (In Russ).]
4. Immunization, vaccines and biologicals. Pneumococcal infection. Available from: http://www.who.int/immu-nization/diseases/pneumococcal/ru/ (accessed: 07/14/2020).
5. Lazareva M.A., Kulichenko T.V., Alyabyeva N.M., et al. Nasopharyngeal carriage of Streptococcus pneumoniae in children from orphanages, preschool institutions and unorganized children under 5 years old // Issues of modern pediatrics. - 2015. - T. 14. - No. 2. - P. 246-255.
6. Pneumococcal conjugate vaccines for infants and children under 5 years of age: WHO position paper, February 2019 // https://www.who.int/immunizationPP pneumococcal 2019 RU.
7. Somova A.V., Romanenko V.V., Golubkova A.A. Epidemiology of S. pneumoniae-associated pneumonia and analysis of the effectiveness of vaccination against pneumococcal infection in children under 6 years old // Epidemiology and vaccine prevention. - 2018. - T. 17. - No. 1. - P. 25-32.
8. Troeger C, Blacker B, Khalil IA, et al. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 19902016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect Dis. 2018; 18(11): 1191—1210. doi: https://doi.org/10.1016/S1473-30 99(18)30310-4
9. Pneumococcal Disease. Surveillance and Reporting. Available from: https://www.cdc.gov/pneumococcal/surveillance.html (accessed: 07/14/2020).
10. European Center for Disease Prevention and Control. Invasive pneumococcal disease. In: ECDC. Annual epidemiological report for 2017. Stockholm: ECDC; 2019. Available from: https://www. ecdc.europa.eu/en/publications-data/invasive-pneumococcal-dis-ease-annual-epidemiological-report-2017 (accessed: 07/14/2020).
11. Ouldali N, Varon E, Levy C, et al. Invasive pneumococcal disease incidence in children and adults in France during the pneumococcal conjugate vaccine era: an interrupted time-series analysis of data from a 17-year national prospective surveillance study. Lancet Infect Dis. 2020;21(1):137-147. doi: https://doi.org/10.1016/S1473-3099(20)30165-1
12. Desmet S, Lagrou K, Wyndham-Thomas C, et al. Dynamic changes in pediatric invasive pneumococcal disease after sequential switches of conjugate vaccine in Belgium: a national retrospective observational study. Lancet Infect Dis. 2021;21(1):127-136. doi: https://doi .org/10.1016/S1473-3099(20)30173-0.
