El consentimiento informado en el menor maduro: comprensión y capacidad de decisión / The informed consent in the mature minor: Understanding and decision-making capacity

Introducción: El consentimiento informado del menor es un requerimiento fundamental de la investigación pediátrica. Actualmente existe una desarmonización en cuanto a la edad del menor maduro para consentir y no se dispone de herramientas sistemáticas para evaluar la competencia en la capacidad de decisión. El objetivo de este trabajo es analizar la situación ética y legal del consentimiento en menores, así como los estudios que utilizan un instrumento objetivo de evaluación en el menor maduro.Material y métodos: Revisión bibliográfica de artículos científicos en PubMed, Embase y Literatura gris, publicados con palabras clave «informed consent minors», sin restricción de fecha hasta marzo 2019. Se revisaron los abstracts y una selección de los artículos completos siguiendo un protocolo de identificación, cribado, elegibilidad e inclusión.Resultados: De los 260 registros identificados, se excluyeron 139. Tras categorizar los 121 artículos resultantes, finalmente se seleccionaron 13 siguiendo los criterios de elegibilidad, incluyéndose 7 artículos sobre normativa ética y legal internacional, y 6 sobre evaluación de comprensión y capacidad de decisión. En 4 estudios se ha utilizado la entrevista semiestructurada McCarthur Competency Assessment Tool for Clinical Research (MacCAT-CR), en diferentes rangos de edad (6-21 años), niños sanos y con alguna patología.Conclusiones: La entrevista semiestructurada McCarthur adaptada a adolescentes podría ser una herramienta adecuada con medidas psicométricas robustas para la valoración de competencia para el consentimiento informado de menores entre 9 y 12 años. La regulación del consentimiento informado en investigación pediátrica debería ser receptiva a estas evidencias. (AU)

Introduction: The informed consent of the minor is a fundamental requirement of paediatric research. There is a lack of harmonisation as regards the age of the mature minor to consent, and there are no systematic tools available to assess competence in decision-making capacity. The objective of this work is to analyse the ethical and legal situation of consent by minors, as well as studies that use an objective assessment tool in the mature minor.Material and methods: Systematic review of scientific articles in PubMed, Embase and the Grey Literature, published with keywords “informed consent minors”, without date restriction until March 2019. Abstracts and a selection of complete articles were reviewed following a protocol including identification, screening, eligibility, and inclusion.Results: Of the 260 records identified, 139 were excluded. After categorising the resulting 121 publications, 13 were finally selected following the eligibility criteria, including 7 articles on international ethical and legal regulations and 6 on understanding and decision- making capacity assessment. The MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) semi-structured interview was used in 4 studies, including different age ranges (6-21 years) in healthy and sick children.Conclusions: The semi-structured MacArthur interview adapted to adolescents could be an appropriate tool with robust psychometric measures for assessing competence for the informed consent of minors between 9 and 12 years of age. The regulation of informed consent in paediatric research should consider this evidence. (AU)

The informed consent in the mature minor: Understanding and decision-making capacity.

INTRODUCTION: The informed consent of the minor is a fundamental requirement of paediatric research. There is a lack of harmonisation as regards the age of the mature minor to consent, and there are no systematic tools available to assess competence in decision-making capacity. The objective of this work is to analyse the ethical and legal situation of consent by minors, as well as studies that use an objective assessment tool in the mature minor. MATERIAL AND METHODS: Systematic review of scientific articles in PubMed, Embase and the Grey Literature, published with keywords "informed consent minors", without date restriction until March 2019. Abstracts and a selection of complete articles were reviewed following a protocol including identification, screening, eligibility, and inclusion. RESULTS: Of the 260 records identified, 139 were excluded. After categorising the resulting 121 publications, 13 were finally selected following the eligibility criteria, including 7 articles on international ethical and legal regulations and 6 on understanding and decision- making capacity assessment. The MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) semi-structured interview was used in 4 studies, including different age ranges (6-21 years) in healthy and sick children. CONCLUSIONS: The semi-structured MacArthur interview adapted to adolescents could be an appropriate tool with robust psychometric measures for assessing competence for the informed consent of minors between 9 and 12 years of age. The regulation of informed consent in paediatric research should consider this evidence.

[The informed consent in the mature minor: Understanding and decision-making capacity]. / El consentimiento informado en el menor maduro: comprensión y capacidad de decisión.

INTRODUCTION: The informed consent of the minor is a fundamental requirement of paediatric research. There is a lack of harmonisation as regards the age of the mature minor to consent, and there are no systematic tools available to assess competence in decision-making capacity. The objective of this work is to analyse the ethical and legal situation of consent by minors, as well as studies that use an objective assessment tool in the mature minor. MATERIAL AND METHODS: Systematic review of scientific articles in PubMed, Embase and the Grey Literature, published with keywords "informed consent minors", without date restriction until March 2019. Abstracts and a selection of complete articles were reviewed following a protocol including identification, screening, eligibility, and inclusion. RESULTS: Of the 260 records identified, 139 were excluded. After categorising the resulting 121 publications, 13 were finally selected following the eligibility criteria, including 7 articles on international ethical and legal regulations and 6 on understanding and decision- making capacity assessment. The MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) semi-structured interview was used in 4 studies, including different age ranges (6-21 years) in healthy and sick children. CONCLUSIONS: The semi-structured MacArthur interview adapted to adolescents could be an appropriate tool with robust psychometric measures for assessing competence for the informed consent of minors between 9 and 12 years of age. The regulation of informed consent in paediatric research should consider this evidence.

Hepatitis B response of premature infants after primary and booster immunisation with a diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/haemophilus influenzae type B vaccine.

A range of schedules are recommended for hepatitis B vaccination of premature infants. This open-label study (217744/083) compared the immune response of premature (N = 94) and full-term infants (N = 92) to hepatitis B antigen following primary administration of hexavalent DTPa-HBV-IPV/Hib vaccine at 2-4-6 months and a booster dose at 18 months. Anti-HBsAg antibodies were determined before and one month after primary and booster doses. There were no significant differences in postprimary seroprotection rates (anti-HBsAg >10 mIU/mL; preterm 93.4%; full-term 95.2%) or geometric mean concentrations (634 versus 867 mIU/ml), and neither appeared to be related to gestational length or birth weight. Prebooster seroprotection rates were 75 and 80.6%, respectively. Six premature infants did not respond to primary and booster doses. Primary and booster vaccinations with DTPa-HBV-IPV/Hib elicit satisfactory anti-HBsAg responses in preterm infants, which are not influenced by gestational age or birth weight. This schedule and vaccine will greatly facilitate the immunisation of premature infants.

Immunogenicity and reactogenicity of a booster dose of a novel combined Haemophilus influenzae type b-Neisseria meningitidis serogroup C-tetanus toxoid conjugate vaccine given to toddlers of 13-14 months of age with antibody persistence up to 31 months of age.

BACKGROUND: A combined Haemophilus influenzae type b and Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine (Hib-MenC-TT) may be a convenient alternative to separate Hib and MenC conjugate vaccines. METHODS: Healthy infants randomized in a previous study for priming at 2, 4, and 6 months: Hib-MenC-TT primed group, 3 doses of Hib-MenC-TT + DTPa-HBV-IPV (N = 87); MenC-TT primed group, 2 doses of MenC-TT (NeisVac-C; Baxter Healthcare SA, Zuürich, Switzerland) + 3 doses of DTPa/Hib containing vaccines (N = 178); MenC-CRM primed group, 3 doses of MenC-CRM197(Meningitec; Wyeth Corporation Delaware, Madison, NJ) + DTPa-HBV-IPV/Hib (N = 93). At 13-14 months of age, Hib-MenC-TT and MenC-TT primed groups received a Hib-MenC-TT booster dose and the MenC-CRM primed group a booster dose of DTPa-HBV-IPV/Hib. Blood samples were taken before and at 1 and 18 months postbooster. RESULTS: Before the booster dose, persistence of anti-polyribosyl ribitol phosphate (PRP) antibody concentration > or =0.15 microg/mL in the Hib-MenC-TT (96.4%) and MenC-TT (96.1%) primed groups and of MenC bactericidal titers > or =1:8 in the Hib-MenC-TT primed group (96.3%) was statistically significantly higher than in the MenC-CRM primed group (86.4% and 85.4%, respectively). One month after the Hib-MenC-TT booster, 99.2% subjects in the Hib-MenC-TT primed + MenC-TT primed pooled groups had anti-PRP levels > or =1 microg/mL, and 99.6% had SBA-MenC titers > or =1:128. The Hib-MenC-TT booster tended to be less reactogenic than the DTPa-HBV-IPV/Hib control and no serious adverse events related to vaccination were reported. Eighteen months after boosting with Hib-MenC-TT, SBA-MenC titers > or =1:8 persisted in 92.7% subjects and anti-PRP > or =0.15 microg/mL persisted in 99.4%. CONCLUSIONS: Primary immunization with 3 doses of Hib-MenC-TT coadministered with DTPa-HBV-IPV induced antibodies that persisted up to the second year of life. The Hib-MenC-TT booster administered to primed toddlers induced robust and persistent antibody responses to both the Hib and MenC components and had an acceptable safety profile.

Antibody persistence and booster vaccination during the second and fifth years of life in a cohort of children who were born prematurely.

BACKGROUND: These studies assessed the immunogenicity and reactogenicity of booster vaccination with diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-adsorbed conjugated Haemophilus influenzae type b (DTaP-HBV-IPV/Hib) at 18-20 months, and with DTaP during the fifth year of life in children who had been born prematurely (<37 weeks gestation). METHODS: Open-label, parallel group studies in which preterm and full-term subjects primed with DTaP-HBV-IPV/Hib received booster vaccination with DTaP-HBV-IPV/Hib (Infanrix hexa) at 18-20 months and DTaP (Infanrix) at 4 years of age. Immunogenicity was assessed before and 1 month after DTaP-HBV-IPV/Hib dose and 1 month after DTaP administration. Local and general symptoms were recorded for 4 days, unsolicited symptoms for 31 days after each dose. RESULTS: Before the second year booster, Hib, hepatitis-B, and polio type 3 seroprotection rates were higher in the full-term group (antipolyribosyl ribitol phosphate > or =0.15 microg/mL observed in 76.2%/83.6% preterm/full term respectively, anti-HBs > or =10 mIU/mL in 75.0%/80.6% respectively). One month after the DTaP-HBV-IPV/Hib booster, > or =98% in both groups were seroprotected/seropositive for all vaccine antigens, except hepatitis-B in preterms (seroprotection rate 91.6%). By the fifth year hepatitis-B seroprotection rates were 85.3%/70.5% (preterm/full term) in subjects who had previously responded to hepatitis-B vaccination, and seroprotection rates for polio and polyribosyl ribitol phosphate were >95%. No differences between groups were observed after the DTaP booster. Both booster doses were generally well tolerated with minimal differences observed between groups. Local symptoms occurred more frequently after the fifth vaccination at 4 years of age. CONCLUSIONS: Despite trends for lower immune responses to some vaccine antigens in preterm subjects, these findings support undelayed primary and booster vaccination in infants and children born before term. Booster vaccinations with DTaP-HBV-IPV/Hib and DTaP were well tolerated in this susceptible group.

Immunogenicity and reactogenicity of primary immunization with a novel combined Haemophilus influenzae Type b and Neisseria meningitidis Serogroup C-tetanus toxoid conjugate vaccine coadministered with a Diphtheria-tetanus-acellular Pertussis-hepatitis B-inactivated poliovirus vaccine at 2, 4 and 6 months.

BACKGROUND: This phase II study evaluated the immunogenicity and reactogenicity of primary vaccination with a novel Hib-MenC conjugate vaccine (GlaxoSmithKline [GSK] Biologicals) coadministered with DTPa-HBV-IPV (GSK Biologicals) at 2, 4 and 6 months. METHODS: Healthy infants were randomized to receive Hib-MenC coadministered with DTPa-HBV-IPV (N = 117) or MenC-CRM (Wyeth) coadministered with DTPa-HBV-IPV/Hib (GSK Biologicals; N = 120) at 2, 4 and 6 months. Antibody concentrations were measured before vaccination and after doses 2 and 3. Solicited local and general symptoms, unsolicited symptoms and serious adverse events (SAEs) were recorded. RESULTS: All subjects in the Hib-MenC group had seroprotective titers of anti-PRP antibodies (>or=0.15 microg/mL) and SBA-MenC titers (>or=1:8) 1 month after the third dose. These responses were noninferior to those seen in the control group, in which a 99.1% seroprotection rate was observed for both Hib and MenC. At that time, anti-PRP and SBA-MenC GMTs were significantly higher in the Hib-MenC group (12.8 microg/mL and 2467.1 microg/mL, respectively) than in the control group (3.8 microg/mL and 1833.7 microg/mL). High seroprotection rates were already observed after the second dose of Hib-MenC; 96.4% and 100% of subjects were seroprotected to Hib and MenC, respectively. Immune responses to coadministered antigens were unimpaired; seroprotection/vaccine response rates >or=96.5% were recorded postdose 3 in the Hib-MenC group. No differences in reactogenicity were seen between the 2 study groups. CONCLUSIONS: Coadministration of a Hib-MenC conjugate vaccine with DTPa-HBV-IPV is well tolerated and immunogenic, and does not impair the immune response to any of the coadministered antigens.

Antipolyribosyl ribitol phosphate response of premature infants to primary and booster vaccination with a combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus/Haemophilus influenzae type b vaccine.

BACKGROUND: Prematurity may be a risk factor for Haemophilus influenzae type b vaccine failure. This article evaluates the Haemophilus influenzae type b immunogenicity of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenzae type b vaccine in preterm infants (< 37 weeks' gestation). METHODS: This was an open-label, parallel group study. Preterm (N = 94) and term infants (N = 92) received 3 doses of a diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenzae type b vaccine at 2, 4, and 6 months with a booster dose at 18 to 20 months. Antipolyribosyl ribitol phosphate antibody concentrations were determined in serum samples taken before and 1 month after primary and booster vaccination. RESULTS: Postprimary seroprotection rates (antipolyribosyl ribitol phosphate > or = 0.15 microg/mL) were lower in preterm than in term infants (92.5% vs 97.8%), with antipolyribosyl ribitol phosphate geometric mean concentrations of 2.241 vs 4.247 microg/mL. A progressive reduction in immune response to the Haemophilus influenzae type b antigen was observed with decreasing length of gestation and decreasing birth weight when cutoff > or = 1 microg/mL was considered. Prebooster seroprotection rates and antipolyribosyl ribitol phosphate geometric mean concentrations were low in both groups (antipolyribosyl ribitol phosphate > or = 1.0 microg/mL in 10.7% of preterm and 28.4% of term infants). A vigorous response to booster vaccination was seen in both groups, with no differences in postbooster seroprotection rates or antipolyribosyl ribitol phosphate geometric mean concentrations between the 2 groups (antipolyribosyl ribitol phosphate > or = 1.0 microg/mL in 100% of preterm and 98.5% of term infants). CONCLUSIONS: Primary vaccination with a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenzae type b vaccine at 2, 4, and 6 months with a booster dose at 18 to 20 months elicits a satisfactory antipolyribosyl ribitol phosphate response in preterm infants compared with term controls. Immunologic response decreased with decreased gestational age and birth weight.

Antibody persistence after primary vaccination with a hexavalent DTPa-HBV-IPV/HiB vaccine coadministered with a meningococcal C-CRM197 vaccine and response to a DTPa-IPV/HiB booster at 18 months of age.

Children 17-20 months of age (N = 344) received a diphtheria-tetanus toxoids-acellular pertussis (DTPa)-inactivated poliovirus vaccine (IPV)/Haemophilus influenzae (Hib) booster after a 3-dose primary vaccination course with DTPa-hepatitis B vaccine-IPV/Hib plus conjugate meningococcal C vaccine-CRM. Seroprotection rates were >80% (diphtheria, tetanus, hepatitis B, polio and polyribosylribitol phosphate) before and > or =96.6% (diphtheria, tetanus, polio and polyribosylribitol phosphate) after booster vaccination. The booster was well-tolerated (fever >39.5 degrees C after <2% of doses; large swelling reactions after 6.3% of doses).

Immunogenicity and reactogenicity of primary immunization with a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-Haemophilus influenzae type B vaccine coadministered with two doses of a meningococcal C-tetanus toxoid conjugate vaccine.

BACKGROUND: This study evaluated the concurrent use of meningococcal C tetanus conjugate (MenC-TT) vaccine (NeisVac-C) with DTaP-based combinations, according to 2 vaccination schedules, one of which included hepatitis B vaccination at birth (Trial DTaP-HBV-IPV/Hib-097). METHODS: Healthy infants were randomized to receive either DTaP-HBV-IPV/Hib (Infanrix hexa) at 2, 4, and 6 months (N = 115) or HBV at birth followed by DTaP-HBV-IPV/Hib at 2 and 6 months and DTaP-IPV/Hib (Infanrix-IPV Hib) at 4 months (N = 115). In both groups 2 doses of MenC-TT conjugate were coadministered at 2 and 4 months, and compared with 3 doses of MenC-CRM197 conjugate (Meningitec) coadministered at 2, 4, and 6 months with DTaP-HBV-IPV/Hib (N = 120). Antibody concentrations were measured at 2, 6 and 7 months. Solicited local and general symptoms, unsolicited symptoms, and serious adverse events (SAEs) were recorded. RESULTS: All MenC-TT recipients had seroprotective concentrations of anti-PRP antibodies (> or = 0.15 microg/mL) 1 month after the third vaccine dose and all had SBA-MenC titers > or = 1:8 after the second dose of MenC-TT. These responses were noninferior to those seen after 3 doses of DTaP-HBV-IPV/Hib and MenC-CRM. Anti-PRP antibody GMCs were significantly higher in MenC-TT than MenC-CRM vaccinees (7.9, 7.3, 3.8 microg/mL, respectively). Immune responses to all other coadministered antigens were unimpaired, with seroprotection/seropositivity rates > or = 98.1% in MenC-TT vaccinees. All schedules studied were well tolerated, with no differences in reactogenicity between the study groups. CONCLUSIONS: Coadministration of DTaP-HBV-IPV/Hib or DTaP-IPV/Hib with 2 doses of MenC-TT conjugate vaccine is safe, well tolerated, and immunogenic, with no impairment of the response to the coadministered antigens.

Response of preterm newborns to immunization with a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio and Haemophilus influenzae type b vaccine: first experiences and solutions to a serious and sensitive issue.

OBJECTIVE: Preterm infants are at increased risk from infections and should be vaccinated at the usual chronological age. The aim of the study was to evaluate the immunogenicity and reactogenicity of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio and Haemophilus influenzae type b (DTPa-HBV-IPV/Hib) vaccine in preterm infants. METHODS: In a comparative trial, 94 preterm infants between 24 and 36 weeks (mean +/- SD gestational age: 31.05 +/- 3.45 weeks; mean birth weight: 1420 +/- 600 g) and a control group of 92 full-term infants were enrolled to receive 3 doses of a DTPa-HBV-IPV/Hib vaccine at 2, 4, and 6 months. Immunogenicity was assessed in serum samples that were taken before and 4 weeks after primary vaccination. Evaluation of reactogenicity was based on diary cards. RESULTS: All preterm (n = 93) and full-term (n = 89) infants who were included in the immunogenicity analysis had seroprotective titers to diphtheria; tetanus; and polio virus types 1, 2, and 3. The immune response to the Hib and hepatitis B components was lower in preterm than in full-term infants: 92.5% versus 97.8% and 93.4% versus 95.2%, respectively. Vaccine response rates for pertussis antigens were >98.9% in both study groups. Although most geometric mean titers were lower in preterm infants, titers were similar for pertussis, a major threat for premature infants. The vaccine was well tolerated, and there were no differences in reactogenicity between groups. Some extremely immature infants experienced transient cardiorespiratory events within the 72 hours after the first vaccination with no clinical repercussion. CONCLUSIONS: Preterm infants who were immunized with the hexavalent DTPa-HBV-IPV/Hib vaccine at 2, 4, and 6 months displayed good immune response to all antigens. The availability of this vaccine greatly facilitates the vaccination of premature infants.