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High prevalence of hepatitis B virus and low vaccine response in children and adolescents in Northeastern Brazil

ABSTRACT

Children have an increased likelihood of becoming carriers of the chronic hepatitis B virus. A total of 1,381 children and adolescents were assessed in five municipalities of Maranhao State, Brazil, for detection of anti-HBc, HBsAg and anti-HBs serologic markers and sociodemographic and behavioral features. Among those who were HBsAg negative and anti-HBc negative, the proportion of anti-HBs positives was calculated after the individuals had completed the vaccination schedule. The robust variance of the Poisson’s regression model was used in order to have adjusted tables and calculate the prevalence ratio. Multivariate analysis was performed to identify the factors associated with the prevalence of anti-HBc with or without HBsAg and the vaccine response. It was observed that 163 children were anti-HBc positive and nine individuals were HBsAg positive. The factors associated with the infection were: municipality of residence (residing in Morros municipality or Humberto de Campos municipality), residence in a rural area, aged between 13 and 15 years old, and illicit drug use. The percentage of individuals who were anti-HBc negative and received all three doses of the vaccine was 48.5%. Among these, only 276 (38.9%) had antibodies at protective concentrations. In an adjusted analysis, Morros municipality presented an increased positivity of vaccine response (p < 0.001), and the age ranging between 6 and 10 years old presented a reduced frequency of response. This study reveals a high prevalence of current and past HBV infection within the targeted age group which, in addition to the low vaccination coverage and serological responses, raises concerns about the management of prevention measures, especially the quality of vaccination in these locations.

Prevalence; Hepatitis B; Vaccine response; Children

INTRODUCTION

Hepatitis B virus (HBV) has a worldwide distribution and is a major public health problem. An estimated 350 million people worldwide live with the virus, which resulted in 887,000 deaths in 201511. WHO. Hepatitis B. [cited 2023 Mar 21]. Available from: http://www.who.int/news-room/fact-sheets/detail/hepatitis-b
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. HBV infection may lead to severe acute fulminant disease or chronic complications such as liver cirrhosis and hepatocarcinoma. In Brazil, approximately 17,000 new cases are diagnosed and reported per year22. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância, Prevenção e Controle das Infecções Sexualmente Transmissíveis, do HIV/Aids e das Hepatites Virais. Protocolo clínico e diretrizes terapêuticas para hepatite B e coinfecções. Brasília: Ministério da Saúde; 2017. [cited 2023 Mar 21]. Available from: https://www.gov.br/aids/pt-br/centrais-de-conteudo/pcdts/2016/hepatites-virais/pcdt_hepatite_b_270917.pdf/view
https://www.gov.br/aids/pt-br/centrais-d...
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In a population-based prevalence survey of hepatitis A, B, and C virus infections in Brazilian capitals conducted in 2010, it was found that 7.4% of all Brazilian capitals displayed HBV (anti-HBc) exposure markers. Among the group, with ages ranging from 10 to 19 years old, this rate was 1.1%; as for the group aged 20 to 69 years old it was 11.6%. HBsAg was positive in 0.37% of the entire population, 0.05% for the group aged 10 to 19 years old and 0.6% for the group aged 20 to 69 years old33. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Aids, DST e Hepatites Virais. Boletim epidemiológico: hepatites virais. Brasília: Ministério da Saúde; 2011. [cited 2023 Mar 21]. Available from: https://bvsms.saude.gov.br/bvs/periodicos/boletim_hepatites_2011.pdf
https://bvsms.saude.gov.br/bvs/periodico...
, qualifying Brazil as a low-endemicity country.

Children are more likely than adults to become chronic carriers of HBV. Among those infected in the first year of life or at birth, up to 90% become chronic carriers. This percentage decreases with age, being 30–50% for those aged 1 to 5 years old. In adulthood, at least 90% of individuals will recover in the first year of infection11. WHO. Hepatitis B. [cited 2023 Mar 21]. Available from: http://www.who.int/news-room/fact-sheets/detail/hepatitis-b
http://www.who.int/news-room/fact-sheets...
,44. Merrill RM, Hunter BD. Seroprevalence of markers for hepatitis B viral infection. Int J Infect Dis. 2011;15:e78-121.,55. Te HS, Jensen DM. Epidemiology of hepatitis B and C viruses: a global overview. Clin Liver Dis. 2010;14:1-21..

According to the World Health Organization (WHO), with the advent of vaccination, the prevalence of HBV infection around the world in children under the age of 5 years old in 2015 was 1.3%, compared with 4.7% before the vaccination programs11. WHO. Hepatitis B. [cited 2023 Mar 21]. Available from: http://www.who.int/news-room/fact-sheets/detail/hepatitis-b
http://www.who.int/news-room/fact-sheets...
.

In Brazil, the National Immunization Program (PNI) of the Ministry of Health has recommended the universal vaccination of children from birth since 1998. In 2016, through an Information Note66. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doenças Transmissíveis. Nota Informativa No 149, de 2015/CGPNI/DEVIT/SVS/MS: informa as mudanças no Calendário Nacional de Vacinação para o ano de 2016. [cited 2023 Mar 21]. Available from: http://antigo.aids.gov.br/pt-br/legislacao/nota-informativa-no-1492015
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, the Ministry of Health expanded the offer to the population regardless of age and/or vulnerability conditions. The goal of vaccination is seroconversion of anti-HBs with titers greater than 10 mIU/ml77. Drutz JE. Hepatitis B virus immunization in infants, children, and adolescents. UpToDate. [cited 2023 Mar 21]. Available from: https://www.uptodate.com/contents/hepatitis-b-virus-immunization-in-infants-children-and-adolescents
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The complete vaccination schedule is capable of producing protective antibodies in more than 95% of neonates, children and young adults11. WHO. Hepatitis B. [cited 2023 Mar 21]. Available from: http://www.who.int/news-room/fact-sheets/detail/hepatitis-b
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. However, there are host factors (genetic or otherwise) that may influence the vaccine response, which is more effective in newborns, children and adolescents and less immunogenic among the elderly and immunocompromised individuals88. Ferraz ML, Schiavon JL, Silva AE. Hepatologia. 2a ed. São Paulo: Manole; 2009..

In addition to host-specific factors, situations that may affect the vaccine effectiveness may include those related to improper handling of the vaccine, such as loss of conservation, improper vaccination site, noncompliance with vials, maximum opening time, and other logistics-related factors99. Oliveira VC, Gallardo MP, Arcêncio RA, Gontijo TL, Pinto IC. Avaliação da qualidade de conservação de vacinas na atenção primária à saúde. Cien Saude Coletiva. 2014;19:3889-98..

Anti-HBs titers are known to decrease over time. It is estimated that 15 to 50% of children who have responded to the three-dose vaccination schedule will have low or undetectable titers after 5 to 15 years1010. Van Damme P. Long-term protection after hepatitis B vaccine. J Infect Dis. 2016;214:1-3.. Despite this finding, it is already known that as long as there was an initial response, there is no need for booster doses because there is an anamnestic response1111. Poovorawan Y, Chongsrisawat V, Theamboonlers A, Crasta PD, Messier M, Hardt K. Long-term anti-HBs antibody persistence following infant vaccination against hepatitis B and evaluation of anamnestic response: a 20-year follow-up study in Thailand. Hum Vaccin Immunother. 2013;9:1679-84.,1212. Ni YH, Chang MH, Wu JF, Hsu HY, Chen HL, Chen DS. Minimization of hepatitis B infection by a 25-year universal vaccination program. J Hepatol. 2012;57:730-5..

This study was conducted to evaluate the factors associated with HBV infection and vaccine response in children and adolescents aged 1 to 15 years old, living in the municipalities of Axixa, Morros, Icatu, Humberto de Campos and Urbano Santos in Maranhao State, Northeastern Brazil, where the overall prevalence of HBV is 2.3%1313. Cruz-Santos MD, Gomes-Gouvêa MS, Costa-Nunes JD, Malta-Romano C, Teles-Sousa M, Fonseca-Barros LM, et al. High prevalence of hepatitis B subgenotype D4 in Northeast Brazil: an ancient relic from African continent? Ann Hepatol. 2018;17:54-63..

MATERIALS AND METHODS

Our study group for the hepatic diseases of Presidente Dutra University Hospital/Federal University of Maranhao (HUUFMA) noticed a large number of hepatitis B patients coming from certain cities in the Northeast of Maranhao State. This observation led to a population-based study for hepatitis B in the municipalities of Axixa, Morros, Icatu, Urbano Santos and Humberto de Campos between 2013 and 2014. The study included around 3,990 subjects who were over one year old1313. Cruz-Santos MD, Gomes-Gouvêa MS, Costa-Nunes JD, Malta-Romano C, Teles-Sousa M, Fonseca-Barros LM, et al. High prevalence of hepatitis B subgenotype D4 in Northeast Brazil: an ancient relic from African continent? Ann Hepatol. 2018;17:54-63..

The sample was prepared through cluster sampling in two stages: in the first, the census sectors were selected by drawing lots with probability proportional to the population, whereas in the second, individuals were drawn. Thirty census sectors were drawn among the five municipalities. In each census sector, blocks and streets were drawn, in addition to the corners of the blocks to decide on the starting point of data collection. The interviewers traveled clockwise from the starting point until the completion of the predicted samples. All households composed of residents or individuals authorized by their parents were included in the sample. Closed or absent households were visited twice before being replaced with another one.

All individuals, including parents or caregivers, underwent clinical, demographic and epidemiological questionnaires. After this stage, all individuals had their blood samples collected in duplicate and kept in a freezer at -70 °C for serological testing (HBsAg, anti-HBs, and anti-HBc).

The blood samples collected after the interview were submitted to enzyme-linked immunosorbent assay (ELISA) with commercial kits (Diasorin®, Italy) to detect HBsAg, anti-hepatitis B core antigen (anti-HBc) and anti-HBs.

An evaluation was carried out for the completion of this paper from a database of the survey with a sample population of 1,381 individuals aged 1 to 15 years old.

In this population, the prevalence of contact with HBV (anti-HBc positivity) was analyzed. Individuals who were anti-HBc negative (who had no contact with HBV) and possessed a vaccination card at the time of the interview were considered for evaluating the vaccine response, thus proving the complete vaccination for hepatitis B. An anti-HBs concentration equal to or greater than 10mUI/ml was considered as a positive response criterion. The defined age limit of 15 took into account that individuals in this age group had already been vaccinated for HBV (mandatory vaccination started in Brazil in 1998) , in the first year of the study.

Data analysis was performed using STATA version 12 and SPSS version 23.0 software, using the Poisson regression model with robust variance to build adjusted tables and calculate the prevalence ratio.

This study was submitted to the HUUFMA Scientific Committee for analysis by the HUUFMA Research Ethics Committee and received a Consubstantiated Opinion, approved under Nº 253/2011, and under No. 448,731, after the amendment (through Plataforma Brasil) that requested an extension of the length of the project, meeting the requirements of Resolution 466/12 of the National Health Council of the Ministry of Health.

RESULTS

Among 1,381 individuals included in the study, 53.8% were female. The mean age was 8.97 years old (standard deviation ± 3.91). Humberto de Campos municipality had 389 participants (28.17%), followed by Urbano Santos municipality with 311 (22.52%), Morros municipality with 310 (22.45%), Icatu municipality with 186 (13.47%) and Axixa municipality with 185 (13.40%) participants. A total of 64.9% of respondents lived in rural areas. Among these, 60.8% had a family income below an equivalent to one minimum wage. Approximately 75.6% were racially identified as mixed-race, 15.13% white and 9.27% black. The use of illicit drugs was reported by 11.2% of individuals; 5.9% reported current use, and 5.3% reported previous use. A total of 3.1% of the individuals stated that they had already started sexual activity (Table 1). In this population, the vaccination coverage with three recommended doses of the hepatitis B vaccine was present in 53.5% of children, while 40.9% had not received a single dose of the vaccine.

Table 1
Profile of demographic, socioeconomic and epidemiological variables of hepatitis B in individuals aged 1 to 15 years old; Maranhao State, Brazil, 2012–2016 (n = 1,381).

Exposure to the virus (anti-HBc +) was demonstrated in 163 individuals (11.8%). Active infection (HBsAg + and anti-HBc +) was observed in nine individuals (0.65%), who were 66% male and 66% over the age of 10.

The prevalence of exposure to the hepatitis B virus (positive for anti-HBc) reached 20.45% in the 13 to 15-year-old age group, 22.26% in Morros municipality and 14.51% with residents living in rural areas. There were no significant differences regarding ethnicity, family income or sex.

An unadjusted analysis revealed associations between HBV exposure and the following variables: municipality of residence, age, area of residence, consumption of illicit drugs, initiation of sexual activity, number of vaccination doses for hepatitis B (p < 0.001), sharing sharp objects (p = 0.024) and alcohol consumption (p = 0.003) (Table 2).

Table 2
Unadjusted analysis of factors associated with Hepatitis B virus infection (anti-HBc positive) in individuals aged 1–15 years; Maranhao State, Brazil, 2012–2016 (n = 1,381).

These variables were subject to analysis adjusted by the Poisson’s regression model and analyzed for the prevalence ratio with robust variance. An association with ages between 13 and 15 years old was confirmed (PR: 2.33, 95% CI: 1.22–4.46), along with being from the Morros municipality (PR: 6.11, 95% CI: 2, 61–14.34) or Humberto de Campos municipality (PR: 2.96, 95% CI: 1.25–7.01), residing in a rural area (PR: 1.85, 95% CI: 1.29–2,66) and consuming illicit drugs, either when the participant confirmed the use (PR: 2.56, 95% CI: 1.51–4.34) or when the individual refused to answer (PR: 1.48 CI 95%: 1.02–2.16) (Table 3).

Table 3
Multivariate analysis of factors associated with hepatitis B virus infection (anti-HBc positive) in individuals aged 1 to 15 years old; Maranhao State, Brazil, 2012–2016 (n = 1,381).

Among the population studied, 1,218 individuals were aged less than or equal to 15 years old at the beginning of the study and had no active infection markers or were not in contact with the hepatitis B virus (HBsAg or anti-HBc). Among these, 729 (59.9%) were able to confirm their vaccination status with a vaccine card, and as for those, 671 (92.04%) received the complete schedule.

In order to assess the vaccine response, 671 individuals were evaluated (they had undergone the complete vaccination schedule and did not have a marker of previous contact with HBV); 54.25% were female, the mean age was 7.8 years old (standard deviation ± 3.6 years), 74.96% were mixed-race, 15.8% were white, and 9.24% were black. The rural area was represented by 64.53% of the children. Among these, only 261 children (38.9%) developed titers considered to be protective against the disease (anti-HBs ≥ 10 mIU/ml) (Table 4).

Table 4
Profile of the hepatitis B vaccine response in individuals aged 1 to 15 years old; Maranhao State, Brazil, 2012–2016 (n = 671).

The unadjusted analysis identified an association between positive vaccine response, municipality of residence (p < 0.001) and age (p = 0.02) (Table 5). In an adjusted analysis, the Morros municipality showed a higher positivity of vaccine response, and the age group between 6 and 10 years old showed a lower frequency of response (PR: 0.72, 95% CI: 0.58–0.89) (Table 6).

Table 5
Unadjusted analysis of factors associated with vaccine response (anti-HBs positive) in individuals aged 1 to 15 years old; Maranhao State, Brazil, 2012–2016 (n = 671).

Table 6
Multivariate analysis of factors associated with hepatitis B vaccine response (anti-HBs positive) in individuals aged 1 to 15 years old; Maranhao State, Brazil, 2012–2016 (n = 671).

DISCUSSION

This study, carried out with children and adolescents aged 1 to 15 years old in five municipalities in Maranhao State, identified a prevalence of 11.8% of HBV exposure, and among them, nine were active carriers of the virus (0.65%). The result of 11.8% prevalence is much higher than the national and Northeastern region averages for the group aged somewhere between 10 and 19 years old, estimated at 1.1% and 2.1%, respectively, and is comparable with the prevalence within the group aged 20 to 69 (11.6%) in the national average and in the Northeastern region (11.7%)33. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Aids, DST e Hepatites Virais. Boletim epidemiológico: hepatites virais. Brasília: Ministério da Saúde; 2011. [cited 2023 Mar 21]. Available from: https://bvsms.saude.gov.br/bvs/periodicos/boletim_hepatites_2011.pdf
https://bvsms.saude.gov.br/bvs/periodico...
,1414. Souto FJ. Distribution of hepatitis b infection in Brazil: the epidemiological situation at the beginning of the 21st century. Rev Soc Bras Med Trop. 2016;49:11-23.. Other cross-sectional studies indicate variations in the percentage of exposure to the virus or active infection in different populations across the state1515. El Khouri M, Cordeiro Q, Luz DA, Duarte LS, Gama ME, Corbett CE. Endemic hepatitis B and C virus infection in a Brazilian Eastern Amazon region. Arq Gastroenterol. 2010;47:35-41.,1616. Pereira LM, Martelli CM, Merchán-Hamann E, Montarroyos UR, Braga MC, Lima ML, et al. Population-based multicentric survey of hepatitis B infection and risk factor differences among three regions in Brazil. Am J Trop Med Hyg. 2009;81:240-7.. One study carried out in Buriticupu municipality found an even higher prevalence of HBV exposure, reaching 20.5% in individuals up to 20 years of age1515. El Khouri M, Cordeiro Q, Luz DA, Duarte LS, Gama ME, Corbett CE. Endemic hepatitis B and C virus infection in a Brazilian Eastern Amazon region. Arq Gastroenterol. 2010;47:35-41.. As there are no studies that evaluate the general population of the state or specifically the pediatric population, it is not possible to state or rule out whether this prevalence matches that in other municipalities, or whether this region in particular presents an especially worrying situation.

Compared with this study, those conducted in pediatric populations in other regions in Brazil revealed rates that are much lower in the Southern and Southeastern regions, ranging from 0.1% to 3.6% for anti-HBc and 0.02% to 1.8% positivity for HBsAg1717. Ciaccia MC, Moreira RC, Lemos MF, Oba IT, Porta G. Epidemiological, serological and molecular aspects of hepatitis B and C in children and teenagers of municipal daycare facilities schools and schools in the city of Santos. Rev Bras Epidemiol. 2014;17:588-99.; however, when examining the Northern region of the country (the region considered to be the most endemic for HBV in the country), prevalence rates of 23.1% for anti-HBc and 3.6% for HBsAg were found in children under age 15 in the Amazon region, even 19 years after the implementation of the universal vaccination program1818. Braga WS, Castilho MC, Borges FG, Martinho AC, Rodrigues IS, Azevedo EP de, et al. Prevalence of hepatitis B virus infection and carriage after nineteen years of vaccination program in the Western Brazilian Amazon. Rev Soc Bras Med Trop. 2012;45:13-7..

A systematic review of HBV prevalence studies in Brazil (conducted between 1999 and 2015) described that the virus is heterogeneously distributed in different regions of Brazil, ranging from less than 1% to 8%, with nonurban locations in the Northern, Northeastern and Central-Western regions having the highest rates1414. Souto FJ. Distribution of hepatitis b infection in Brazil: the epidemiological situation at the beginning of the 21st century. Rev Soc Bras Med Trop. 2016;49:11-23., reinforcing that regions that are farther away from large centers and scarcely urbanized are more susceptible to HBV infection1919. Katsuragawa TH, Cunha RP, Salcedo JM, Souza DC, Oliveira KR, Gil LH, et al. High seroprevalence of hepatitis B and C markers in the upper Madeira River region, Porto Velho, Rondônia State, Brazil. Rev Pan-Amaz Saude. 2010;1:91-6..

As for the risk factors related to the presence of anti-HBc, it was identified that living in the municipalities of Humberto de Campos and Morros was independently associated with higher rates than those associated with living in Axixa municipality. Although these are adjacent municipalities, according to the Brazilian Institute of Geography and Statistics (IBGE), Axixa municipality has a human development index (HDI) classified as medium, while the other four municipalities covered in the study are classified with low municipal HDI2020. Instituto Brasileiro de Geografia e Estatística. Brasil/Maranhão/Axixá. [cited 2023 Mar 21]. Available from: https://cidades.ibge.gov.br/painel/historico.php?codmun=210110
https://cidades.ibge.gov.br/painel/histo...
. Some studies already indicate that lower socioeconomic indexes are linked to a higher prevalence of HBV infection2121. Toukan AU, Sharaiha ZK, Abu-el-Rub OA, Hmoud MK, Dahbour SS, Abu-Hassan H, et al. The epidemiology of hepatitis b virus among family members in the Middle East. Am J Epidemiol. 1990;132:220-32., probably related to less adequate health services and conditions for the prevention of infectious diseases.

Likewise, residence in a rural area was shown to be associated with infection, probably also reflecting more precarious living conditions and failures in the health care system, which involves early diagnosis of the infection and health education1414. Souto FJ. Distribution of hepatitis b infection in Brazil: the epidemiological situation at the beginning of the 21st century. Rev Soc Bras Med Trop. 2016;49:11-23.,1515. El Khouri M, Cordeiro Q, Luz DA, Duarte LS, Gama ME, Corbett CE. Endemic hepatitis B and C virus infection in a Brazilian Eastern Amazon region. Arq Gastroenterol. 2010;47:35-41.. These conditions make the regions that are more distant or isolated from large centers become endemic areas with an intermediate or high prevalence of HBV infection1414. Souto FJ. Distribution of hepatitis b infection in Brazil: the epidemiological situation at the beginning of the 21st century. Rev Soc Bras Med Trop. 2016;49:11-23..

An elevated frequency of HBV contact markers was observed among individuals aged somewhere between 13 and 15 years old, a fact also observed in a study carried out in a quilombola community in the Northeast of Goias State (a population that is comparable to the one studied here), where a 7.4% prevalence of this marker was found in the group aged 0 to 10, rising to 16.6% in the group aged 11 to 202222. Matos MA, Reis NR, Kozlowski AG, Teles SA, Motta-Castro AR, Mello FC, et al. Epidemiological study of hepatitis A, B and C in the largest Afro-Brazilian isolated community. Trans R Soc Trop Med Hyg. 2009;103:899-905.. This result is probably related to the individual’s insertion in classic risk behaviors, such as the initiation of sexual activity or the use of illicit drugs, observed through all studies conducted with this population of this age group2323. Trépo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet. 2014;384:2053-63..

In fact, the use of illicit drugs also proved to be an independent risk factor for infection, even when the individual refused to answer, suggesting that there may have been non-admission of illicit drug use by the interviewees. However, the majority of individuals in the region who have these habits used non-injecting drugs (mainly marijuana or crack), suggesting that it is an indirect risk factor for other mechanisms of virus transmission, such as unprotected sexual contact, in addition to functioning as a bridge for the later use of injectable drugs2424. Ferreira RC, Rodrigues FP, Teles SA, Lopes CL, Motta-Castro AR, Novais AC, et al. Prevalence of hepatitis B virus and risk factors in Brazilian non-injecting drug users. J Med Virol. 2009;81:602-9.. This issue reinforces the susceptibility of the drug user population as a risk group for infection1414. Souto FJ. Distribution of hepatitis b infection in Brazil: the epidemiological situation at the beginning of the 21st century. Rev Soc Bras Med Trop. 2016;49:11-23.,2323. Trépo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet. 2014;384:2053-63., requiring specific approaches.

Active infection was present in 0.65% of those evaluated. That prevalence is higher than the national average of 0.055% for the 10 to 19 age group and comparable to the 0.6% rate found in the 20 to 69 age group33. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Aids, DST e Hepatites Virais. Boletim epidemiológico: hepatites virais. Brasília: Ministério da Saúde; 2011. [cited 2023 Mar 21]. Available from: https://bvsms.saude.gov.br/bvs/periodicos/boletim_hepatites_2011.pdf
https://bvsms.saude.gov.br/bvs/periodico...
. When evaluating studies carried out abroad, where universal vaccination in children had already been implemented, the results found here were higher than the rates of 0.05%2525. Madani TA. Trend in incidence of hepatitis B virus infection during a decade of universal childhood hepatitis B vaccination in Saudi Arabia. Trans R Soc Trop Med Hyg. 2007;101:278-83. found in children in Saudi Arabia, and those of 0.19% in Germany2626. Cai W, Poethko-Müller C, Hamouda O, Radun D. Hepatitis B virus infections among children and adolescents in Germany: Migration background as a risk factor in a low seroprevalence population. Pediatr Infect Dis J. 2011;30:19-24., but lower than the rates in China (1.6%)2727. Su H, Shao Z, Pu Z, Wang Y, Zhang L, Zhang W, et al. Overt and occult hepatitis B virus infection among community children in Northwest China. J Viral Hepat. 2017;24:797-803., Colombia (2%)2828. de la Hoz F, Perez L, de Neira M, Hall AJ. Eight years of hepatitis B vaccination in Colombia with a recombinant vaccine: factors influencing hepatitis B virus infection and effectiveness. Int J Infect Dis. 2008;12:183-9. and Mexico (3.1%)2929. Escobedo-Meléndez G, Fierro NA, Roman S, Maldonado-González M, Zepeda-Carrillo E, Panduro A. Prevalence of hepatitis A, B and C serological markers in children from western Mexico. Ann Hepatol 2012;11:194-201., indicating the impact of these programs in reducing HBV infection.

The municipalities of Humberto de Campos and Morros were responsible for 77% of the total HBsAg carriers (active infection), suggesting that urgent measures should be prioritized in these locations, such as health education, strict prenatal care to prevent maternal-fetal transmission, and effective vaccination, which plays a fundamental role in controlling HBV infection. In addition to perinatal transmission, horizontal transmission (which occurs through household contact with family members) is more frequent within the pediatric age group3030. Brasil LM, Fonseca JC, Souza RB, Braga WS, Toledo LM. Prevalência de marcadores para o vírus da hepatite B em contatos domiciliares no Estado do Amazonas. Rev Soc Bras Med Trop. 2003;36:565-70.. Low socioeconomic, educational, and hygiene conditions and precarious and overcrowded households are characteristic of this population, which probably increase the spread of HBV infection in this population3131. Motta-Castro AR, Yoshida CF, Lemos ER, Oliveira JM, Cunha RV, Lewis-Ximenez LL, et al. Seroprevalence of hepatitis B virus infection among an afro-descendant community in Brazil. Mem Instituto Oswaldo Cruz. 2003;98:13-7., mainly due to the increase in intra-household percutaneous contact. This reality further highlights the need for vaccination at birth to prevent this infection.

In Brazil, the National Immunization Program (PNI) has made vaccination for hepatitis B mandatory since 1998. Among the population studied, 1,218 individuals were aged less than or equal to 15 years old at the beginning of the study and had no infection markers active or contact with the hepatitis B virus (HBsAg or anti-HBc). Among these, 729 (59.9%) were able to confirm their vaccination status with a vaccine card, and as for those, 671 (92.04%) received the complete schedule. A rate of approximately 60% shows a low rate of vaccination coverage, which, in this population, should reach 100%.

Despite the PNI’s recommendation for vaccination against the hepatitis B virus from birth, no records were found at the State Department of Health with data on vaccination coverage in the municipalities studied in 1998, suggesting a late implementation. The records show an average vaccination coverage from 1999 to 2012 of 70.82% in the region, with Humberto de Campos municipality having the highest average (84.76%), followed by Axixa municipality (79.9%). The discrepancy shown here may also be related to the fact that some individuals may have been submitted to the vaccine but did not present their card for confirmation at the time of the study. The most alarming finding was that only 38.9% of children vaccinated with three doses had protective concentrations of the antibody.

The effectiveness of the HBV vaccine has been proven in many studies worldwide and in Brazilian studies within the pediatric population1212. Ni YH, Chang MH, Wu JF, Hsu HY, Chen HL, Chen DS. Minimization of hepatitis B infection by a 25-year universal vaccination program. J Hepatol. 2012;57:730-5.,3232. Bruce MG, Bruden D, Hurlburt D, Zanis C, Thompson G, Rea L, et al. Antibody levels and protection after hepatitis B vaccine: results of a 30-year follow-up study and response to a booster dose. J Infect Dis. 2016;214:16-22.,3333. Coppola N, Corvino AR, De Pascalis S, Signoriello G, Di Fiore E, Nienhaus A, et al. The long-term immunogenicity of recombinant hepatitis B virus (HBV) vaccine: contribution of universal HBV vaccination in Italy. BMC Infect Dis. 2015;15:149.. In another study carried out in Sao Paulo State, birth weight had an influence on the vaccine response; among those assessed who were born weighing more than 1,500 g, seroconversion was 100%, compared with 75% seroconversion for the group equal to or less than 1,500 g at birth3434. Motta MS, Mussi-Pinhata MM, Jorge SM, Yoshida CF, Souza CB. Immunogenicity of hepatitis B vaccine in preterm and full term infants vaccinated within the first week of life. Vaccine. 2002;20:1557-62..

It is known that failures in response (in healthy people) may be associated with genetic characteristics or the result of technical errors with the vaccine, such as administration or failure in packaging, both during transport and at the final destination3535. Sadeck LS, Ramos JL. Immune response of preterm infants to hepatitis B vaccine administered within 24 hours after birth. J Pediatr (Rio J). 2004;80:113-8.

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https://www.uptodate.com/contents/hepati...
-3737. Tonnis WF, Amorij JP, Vreeman MA, Frijlink HW, Kersten GF, Hinrichs WL. Improved storage stability and immunogenicity of hepatitis B vaccine after spray-freeze drying in presence of sugars. Eur J Pharm Sci. 2014;55:36-45..

In Brazil, Oliveira et al.99. Oliveira VC, Gallardo MP, Arcêncio RA, Gontijo TL, Pinto IC. Avaliação da qualidade de conservação de vacinas na atenção primária à saúde. Cien Saude Coletiva. 2014;19:3889-98. evaluated the quality of vaccinations for primary health care in 261 vaccination rooms in Minas Gerais State. They observed that the degree of conservation of the vaccines was not adequate in 59.3%, and 26.9% had a critical degree of quality, pointing to the need for training human resources, monitoring and evaluating the work process. Therefore, the low vaccine efficacy found in our study could be related to these factors, which could indirectly mirror the deficient socioeconomic indexes of the cities studied.

This speculation can be reinforced by the finding that the results were different among the municipalities studied, which may suggest that health promotion actions reflect the reality of each municipality, generating different results.

Another common situation, which could justify the result of low effectiveness found here, is the drop in anti-HBs titers that normally occurs with advancing age after vaccination1010. Van Damme P. Long-term protection after hepatitis B vaccine. J Infect Dis. 2016;214:1-3.,1212. Ni YH, Chang MH, Wu JF, Hsu HY, Chen HL, Chen DS. Minimization of hepatitis B infection by a 25-year universal vaccination program. J Hepatol. 2012;57:730-5.,3838. Fagundes GD, Tabalipa FO, Silva J. Antibody levels in children after 10 years of vaccination against hepatitis B : a Brazilian community-based study. Rev Soc Bras Med Trop. 2012;45:260-2.. A study of vaccinated children followed for 10 years found protective titers in 54.8% of the children3838. Fagundes GD, Tabalipa FO, Silva J. Antibody levels in children after 10 years of vaccination against hepatitis B : a Brazilian community-based study. Rev Soc Bras Med Trop. 2012;45:260-2.. To assess this possibility, analyses were performed comparing three age groups (1 to 5, 6 to 10 and 11 to 15 years old), and unexpectedly, the group aged between 6 and 10 was the one with the lowest rate of effective results, showing that it is unlikely that the low level of effectiveness identified is related to a progressive decline related to age.

It could be speculated that the lower response rate observed for the group aged between 6 and 10 years old is related to failures in health promotion policies in the state between 2004 and 2008, which could be reflected in these results and was already independent of the municipality studied.

Regarding the natural decline in antibodies with age, studies in other countries have shown conflicting results. A prospective cohort study conducted by Bruce et al.3232. Bruce MG, Bruden D, Hurlburt D, Zanis C, Thompson G, Rea L, et al. Antibody levels and protection after hepatitis B vaccine: results of a 30-year follow-up study and response to a booster dose. J Infect Dis. 2016;214:16-22. in Alaska concluded that vaccine protection continues for more than 30 years, and that more than 94% of people in the study had evidence of protection. In contrast to this, in a study carried out in the USA3939. Middleman AB, Baker CJ, Kozinetz CA, Kamili S, Nguyen C, Hu DJ, et al. Duration of protection after infant hepatitis B vaccination series. Pediatrics. 2014;133:e1500-7., in which 420 adolescents were aged between 16 and 19 years old, 76% had anti-HBs < 10 mIU/ml. Nevertheless, there is already sufficient knowledge to determine that there is no need for booster doses of the vaccine for healthy individuals who had a satisfactory response after vaccination4040. Lu CY, Ni YH, Chiang BL, Chen PJ, Chang MH, Chang LY, et al. Humoral and cellular immune responses to a hepatitis B vaccine booster 15–18 years after neonatal immunization. J Infect Dis. 2008;197:1419-26..

A prospective study evaluating these factors is being conducted by our group to identify whether they could be important in our population regarding the effectiveness of the HBV vaccine.

CONCLUSION

In conclusion, this study showed a high prevalence rate of active carriers and of previous contact with HBV in this age group in the region studied, and the effectiveness of the vaccine was lower than expected. These findings highlight the need to implement urgent measures to prevent infection among this population and are evidence that studies must be carried out to identify the real situation in the entire Maranhao State.

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  • FUNDING: This work was supported by Fundacao de Amparo a Pesquisa do Estado do Maranhao (FAPEMA), grants Nº PPSUS-03348/13 and PPP-01263/12, and by Brazilian Ministry of Health, grant Nº 1/2013.

Publication Dates

  • Publication in this collection
    21 Apr 2023
  • Date of issue
    2023

History

  • Received
    21 Dec 2022
  • Accepted
    21 Feb 2023
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