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.

Immunogenicity in sheep of Uruguayan commercial vaccines against bovine alphaherpesvirus 1, 5 and bovine pestiviruses / Imunogenicidade em ovelhas de vacinas comerciais Uruguaias para alfaherpesvírus bovino 1, 5 e pestivírus de bovinos

ABSTRACT: The serological responses induced by four commercial inactivated Uruguayan vaccines against bovine alphaherpesviruses (BoHV)-1 and -5 and bovine pestiviruses (BVDV-1, BVDV-2, and HoBiPeV) were evaluated in sheep. Thirty-seven sheep were immunized twice (day 0 and 25) and their serum samples were tested at different intervals (days 0, 25, 40, 60, and 90) post-vaccination (PV). Among the four vaccines tested, only one (G4) could induce the production of moderate neutralizing antibody titers against BoHV-1 and -5 and BVDV-1 and -2. The G3 vaccine showed a neutralizing serological response against the bovine alphaherpesviruses only. The G1 and G2 vaccines produced extremely low levels of antibodies in a few vaccinated animals only (geometric mean titers (GMT) 2.2). Similar levels of immunological responses were induced by the G4 vaccine against BoHV-1 and -5, and titers of neutralizing antibodies induced in approximately 70% of the animals are known to confer protection (GMT > 8). For bovine pestiviruses, the vaccine stimulated response of G4 against BVDV-2 was higher compared to that against BVDV-1, and extremely low for HoBiPeV. The peak of neutralizing antibodies to BoHV-1 and BVDV-1 was observed on days 40 and 60 PV, respectively. Thereafter, a remarkably decrease in neutralizing antibody response was observed at day 90 PV. These results demonstrated that tested commercial Uruguayan vaccines did not induce a serological response of adequate magnitude and duration. Thus, it is important to periodically review formulations and compositions of commercial vaccines against bovine alphaherpesviruses and pestiviruses.

RESUMO: A resposta sorológica induzida por quatro vacinas comerciais uruguaias inativadas contra os alfaherpesvírus bovinos (BoHV-1 e -5) e pestivírus de bovinos (BVDV-1, BVDV-2 e HoBiPeV) foi avaliada em ovinos. Os animais foram imunizados duas vezes (dia 0 e dia 25) e o soro testado em diferentes intervalos (dias 0, 25, 40, 60 e 90) após a vacinação (PV). Dentre as quatro vacinas testadas, apenas uma (G4) apresentou títulos de anticorpos neutralizantes moderados para os BoHV-1 e -5, BVDV-1 e 2. A vacina G3 apresentou resposta somente para alfaherpesvírus bovinos. As vacinas G1 e G2 estimularam resposta somente em alguns animais vacinados. Para a vacina G4, observou-se que a resposta imunológica frente ao BoHV-1 e 5 foi semelhante e pelo menos 70% dos animais apresentaram níveis protetivos de anticorpos neutralizantes. Para os pestivírus bovinos, a vacina G4 estimulou resposta para o BVDV-2 mais elevada quando comparada com o BVDV-1, e quase que indetectável para HoBiPeV. O pico de anticorpos neutralizantes para o BoHV-1 foi observado no dia 40 PV e no dia 60 PV para o BVDV-1. Após isso, observou-se um decréscimo considerável na resposta de anticorpos neutralizantes. Os resultados demonstraram que vacinas comerciais uruguaias testadas não induziram resposta sorológica de magnitude e duração adequadas. Assim, ressalva-se a importância de rever periodicamente a formulação e composição das vacinas comerciais para alfaherpesvírus e pestivírus bovinos.

Serological response against bovine herpesvirus and bovine viral diarrhea virus induced by commercial vaccines in Holstein heifers / Resposta sorológica contra herpesvírus bovino e vírus da diarreia viral bovina induzida por vacinas comerciais em novilhas Holandesas

Vaccination is a strategy to the prevention and control of reproductive diseases caused by bovine viral diarrhea virus (BVDV) and bovine herpesvirus type 1 (BoHV-1), however the various compositions of commercial vaccines should be evaluated for their ability to induce protection mediated by antibodies. The objective of this research was to evaluate the production of specific neutralizing Abs against BVDV-1 and 2, and BoHV-1 induced by commercial vaccines composed by different adjuvants. Holstein heifers were vaccinated and distributed in three experimental groups: Group I (G1) was vaccinated with a commercial vaccine containing inactivated BVDV-1, BVDV-2 and BoHV-1 diluted in alum hydroxide as adjuvant (n=9); Group II (G2) was vaccinated with an product containing inactivated strains of BVDV-1, BVDV-2, BoHV-1 and BoHV-5 diluted in oil emulsion as adjuvant (n=10); Group III (G3) was vaccinated with a commercial vaccine containing inactivated BVDV-1 and BVDV-2, besides live modified thermosensitive BoHV-1, diluted in Quil A, amphigen and cholesterol (n=10); A control, non-vaccinated group (n=6) was mock vaccinated with saline. Heifers received two subcutaneous doses of 5mL of each commercial vaccine on the right side of the neck, with 21 days interval. Humoral immune response was assessed by the virus neutralization test (VN) against BVDV-1 (NADL and Singer strains), BVDV-2 (SV253 strain) and BoHV-1 (Los Angeles strain) in serum samples collected on vaccination days zero (D0), 21 (D21) and 42 (D42; 21 days after boosting). Neutralizing Abs against BVDV-1 NADL was detected only in D42, regardless of the vaccine used. Similar geometric mean titers (GMT) for BVDV-1 NADL were observed between G1 (log2=5.1) and G3 (log2=5.1). The seroconversion rate (%) was higher in G1 (78%) when compared to G2 (10%) and G3 (40%). For BVDV-1 Singer, it was also possible to detect Abs production in G1 (log2=5.8, 100% seroconversion rate) and G3 (log2=3.5, seroconversion rate = 60%), only after the booster dose (D42). Neutralizing Abs to BVDV-2 (SV253) were detected only in G3, observing 90% seroconversion associated with high titers of Abs (log2=6.7) after the 2nd dose of vaccine (D42). Heifers from G1 and G3 responded to BoHV-1 after the first dose (D21): G1 (log2=2.5, seroconversion rate = 67%) and G3 (log2=0.7, seroconversion rate = 80%). In D42, a higher magnitude response was observed in the heifers from G3 (log2=6.1, 100%) compared with G1 (log2=4.3, 100%) and G2 (log2=2.7, 60%). Based on the data obtained, it can be concluded that the commercial vaccine contained aluminum hydroxide (G1) was most effective in the induction of antibodies against BVDV-1. On the other hand, this vaccine did not induce the production of neutralizing Abs against BVDV-2. Only the heifers from G3 (Quil A, amphigen and cholesterol) generated neutralizing Abs against BVDV-2. The animals that received commercial vaccine containing oil emulsion as adjuvant (G2) had a weak/undetectable response against BVDV-1 and BVDV-2. The best protective response against BoHV-1 was observed in heifers vaccinated with the live modified thermosensitive virus.(AU)

A vacinação é utilizada como estratégia para a prevenção e controle das doenças reprodutivas, causadas pelos vírus da diarreia viral bovina (BVDV) e herpesvírus bovino tipo 1 (BoHV-1), entretanto, as diversas composições de vacinas comerciais devem ser avaliadas quanto a sua eficiência protetiva mediada por anticorpos (Acs). O objetivo desta pesquisa foi avaliar a produção Acs neutralizantes específicos para cepas de BVDV-1 e 2, e BoHV-1 induzida por vacinas comerciais contendo diferentes tipos de adjuvantes. Para tal, novilhas Holandesas foram vacinadas e distribuídas em três grupos experimentais: Grupo I (G1) foi vacinado com uma vacina comercial composta por cepas inativadas de BVDV-1, BVDV-2 e BoHV-1 diluídas em hidróxido de alumínio como adjuvante (n=9); Grupo II (G2) foi vacinado com produto contendo as cepas inativadas de BVDV-1, BVDV-2, BoHV-1 e BoHV-5 em uma emulsão oleosa como adjuvante (n=10); O Grupo III (G3) foi vacinado com uma vacina comercial contendo BVDV-1 e BVDV-2 inativado, além do BoHV-1 vivo modificado e termosensivel, diluídos em adjuvante contendo Quil A, Amphigem e colesterol (n=10); O Grupo Controle não vacinado (n=6) foi inoculado com solução salina. As novilhas receberam duas doses das respectivas vacinas ou solução salina (5mL), com intervalo de 21 dias, por via subcutânea, na tábua do pescoço do lado direito. A resposta imune humoral foi avaliada pelo teste de vírus neutralização (VN) contra o BVDV-1 (cepas NADL e Singer), BVDV-2 (cepa SV253) e BoHV-1 (cepa Los Angeles) em amostras de soro coletadas nos dias (D) de vacinação zero (D0), 21 dias após 1ª dose (D21)e 42 (D42; 21 dias após A 2ª dose). Os anticorpos neutralizantes contra o BVDV-1 NADL foram detectados apenas em D42, independentemente da vacina utilizada. Os títulos médios geométricos (GMT) de anticorpos foram semelhantes entre G1 (log2=5,1) e G3 (log2=5,1). A taxa de soroconversão foi maior no G1 (78%) quando comparado ao G2 (10%) e G3 (40%). Para o BVDV-1 Singer, somente após D42 foi observada a produção de Acs no G1 (log2=5,8; taxa de soroconversão de 100%) e G3 (log2=3,5; taxa de soroconversão = 60%). Os anticorpos contra BVDV-2 (SV253) foram detectados apenas nas novilhas do G3, observando-se taxa de soroconversão de 90% com altos títulos de anticorpos neutralizantes (log2=6,7) em D42. Novilhas G1 e G3 responderam ao BoHV-1 após a primeira dose (D21): G1 (log2=2,5; taxa de seroconversão = 67%) e G3 (log2=0,7; taxa de seroconversão = 80%). Em contrapartida, foi observada uma maior magnitude de resposta para as novilhas G3 (log2=6,1; 100%) em D42, em relação aos animais G1 (log2=4,3; 100%) e G2 (log2=2,7; 60%). Com base nos dados obtidos, foi possível concluir que a vacina composta por hidróxido de alumínio (G1) foi mais eficaz na produção de anticorpos contra o BVDV-1, em contrapartida esse produto não induziu anticorpos contra o BVDV-2. Apenas as novilhas do G3 (Quil A, amphigen e colesterol) geraram Acs neutralizantes contra o BVDV-2. Os animais que receberam a vacina em emulsão oleosa (G2) como adjuvante apresentaram uma resposta fraca/indetectável contra o BVDV-1 e BVDV-2. A melhor resposta protetiva contra o BoHV-1 foi observada nas novilhas vacinadas com a vacina viva modificada termosensível.(AU)

Effects of Interleukin-4 and Interleukin-12b Gene Polymorphisms on Hepatitis B Virus Vaccination

Abstract: Approximately 10% of individuals do not respond to hepatitis B virus (HBV) vaccination, i.e. non-responders (NRs). We aimed to investigate the association of interleukin (IL)-4 and IL-12B gene polymorphisms with responsiveness to the HBV vaccine in Korean infants. Among 300 healthy infants (9-12 month), SNPs for the IL-4 gene (rs2243250, rs2070874, and rs2227284) and for the IL-12B gene (rs3213094 and rs17860508) were compared between subgroups in terms of the response to HBV vaccination. The percentages of NRs (< 10 mIU/mL), low-titer responders (LRs, 10-100 mIU/mL), and high-titer responders (HRs, ≥ 100 mIU/mL) were 20.3%, 37.7% and 42.0%, respectively. No SNPs differed in frequency between NRs and responders or between LRs and HRs. We divided the subjects into two groups according to the time interval from the 3rd dose of HBV vaccination to Ab quantification: > 6 months from the 3rd dose (n = 87) and ≤ 6 months from the 3rd dose (n = 213). In the ≤ 6 month subjects, rs2243250C and rs2227284G were significantly frequent in the lower-titer individuals (NRs + LR) than HRs (40.1 vs. 25.9%, p = 0.014 and 45.1 vs. 33.0%, p = 0.018, respectively), and the rs2243250C and rs2227284G frequencies were significantly different among the three subgroups (13.2 vs. 26.9 vs. 25.9%, p = 0.040 and 15.5 vs. 29.6 vs. 33.0%, p = 0.038, respectively). In conclusion, those results suggest that IL-4 gene polymorphisms may play a role in the response to the HBV vaccine in Korean infants.

Resposta sorológica aos herpesvirus bovino tipos 1 e 5 e vírus da diarreia viral bovina induzida por vacinas comerciais / Serological response to bovine herpesvírus 1 and 5 and bovine viral diarrea virus induced by comercial vaccines

Este trabalho avaliou a imunogenicidade de vacinas para os herpesvírus bovino 1 e 5 (BoHV-1, BoHV-5) e vírus da diarreia viral bovina 1 e 2 (BVDV-1, BVDV-2), disponíveis no mercado brasileiro. Para isso, novilhos de raças de corte foram alocados em grupos de 10-12 animais e vacinados duas vezes, com intervalo de 30 dias, com cada uma das oito vacinas disponíveis. Amostras de soro coletadas 30 dias após a segunda dose foram submetidas ao teste de virusneutralização (VNT), frente a cepas de BoHV-1, BoHV-5, BVDV-1 e BVDV-2. Com exceção de duas vacinas que induziram soroconversão em 8/10 e 9/10 dos animais, as demais induziram anticorpos neutralizantes contra o BoHV-1 em todos os animais vacinados (títulos médios geométricos [GMTs] entre 1,7 e 4,8). Quatro vacina s induziram anticorpos reagentes com o BoHV-5 em todos os animais (GMTs de 1,0 a 4,2), enquanto três vacinas induziram soroconversão parcial em 5/10, 6/10 e 7/10 animais. Apenas uma vacina induziu resposta sorológica detectável frente ao BVDV-1 em todos os animais vacinados (GMT=6,7). Soroconversão parcial ao BVDV-1 foi detectada em quatro grupos vacinais (6/10, GMT 4,0 6/10, GMT 5,6 e 4/10, GMT 1,8). Uma vacina induziu resposta em apenas um animal (título de 40) e três vacinas não induziram anticorpos detectáveis contra o BVDV-1 em nenhum animal. Atividade neutralizante frente ao BVDV-2 foi detectada apenas em três grupos vacinais, e parcialmente (10/10, GMT 6,5; 5/10, GMT 1,6 e 2/10, GMT 1,0). Cinco vacinas não induziram atividade neutralizante detectável frente ao BVDV-2 em nenhum dos animais imunizados. Esses resultados demonstram que o componente BoHV-1 da maioria das vacinas comerciais possui imunogenicidade adequada. No entanto, o componente BVDV da grande maioria das vacinas não induz resposta neutralizante consistente frente ao BVDV-1 e, ...

This study evaluated the immunogenicity of vaccines for bovine herpesvirus 1 and 5 (BoHV-1/5) and viral diarrhea virus 1 and 2 (BVDV-1/2) available in the Brazilian market. Calves were divided into groups (10-12), vaccinated twice with a 30 days interval. Samples collected 30 days after the second dose were submitted to virus neutralization test against BoHV-1, BoHV-5, BVDV-1 and BVDV-2. With the exception of two vaccines that induced seroconversion in 8/10 and 9/10 of the animals, the other induced antibodies against BoHV-1 in all vaccinated animals (geometric mean titers [GMTs] 1.7 and 4.8) and four induced antibodies against BoHV-5 in all animals (GMTs 1.0 to 4.2), whereas three vaccines induced partial seroconversion (5/10, 6/10 and 7/10 animals). Only one vaccine induced antibody response to BVDV-1 in all vaccinated animals (GMT=6.7). Partial seroconversion to BVDV-1 was detected in four vaccine (6/10, GMT 4.0; 6/10, GMT 5.6 and 4/10, GMT 1.8). A vaccine induced response in only one animal and three vaccines did not induce antibodies against BVDV-1 in any animal. Antibodies to BVDV-2 were detected only in three vaccine groups, and partly (10/10, GMT 6.5; 5/10, GMT 1.6 and 2/10, GMT 1.0). Five vaccines did not induce antibodies to BVDV-2 in any of the animals. Results demonstrate that the BoHV-1 component of commercial vaccines seems to have acceptable immunogenicity. However, the BVDV component of most vaccines does not induce consistent response against BVDV-1, especially, to BVDV-2. It is evident that strategies for production of vaccines, particularly to BVDV must be urgently revised.