Javier Arístegui

Immunogenicity and safety of AS03-adjuvanted 2009 influenza A H1N1 vaccine in children 6-35 months.

We report on the evaluation of the immunogenicity and reactogenicity/safety of AS03-adjuvanted vaccine against pandemic influenza A/H1N1/2009 in young children. In this open-label, randomized study, 157 healthy children aged 6-35 months received two doses (21 days apart) of split-virion inactivated A/California/7/2009 H1N1 vaccine containing either (i) 1.9microg hemagglutinin (HA) and AS03(B) (5.93mg tocopherol) (N=104) or (ii) 3.75mug HA and AS03(A) (11.86mg tocopherol) (N=53). At 21 days following the first dose of AS03(B)-adjuvanted vaccine (1.9microg HA) the percentage of children with hemagglutination-inhibition titers of >or=40 against the vaccine strain rose from 3.0% before vaccination to 100%. The seroconversion rate was 99% and the geometric mean titer (GMT) increased from 6 to 313. After the second dose the GMT increased further to 2008. The higher dose AS03(A)-adjuvanted 3.75microg HA vaccine did not further increase the immune response. Solicited symptoms reported within 7 days following vaccination were mainly mild to moderate. After the first dose of AS03(B)-adjuvanted vaccine (1.9microg HA) the most common solicited symptoms were pain at the injection site (35.6%) and irritability (31.7%). Fever (axillary >or=37.5 degrees C) was reported with an incidence of 20.2%. After the second dose reactogenicity tended to increase (injection site pain: 41.3%; irritability: 46.2%; fever >or=37.5 degrees C: 67.3%). Spontaneously reported adverse events with an intensity that prevented normal activities were documented for 2.9-6.7% of doses with only one event (vomiting) considered related to vaccination. There was one serious adverse event reported in the AS03(A)-adjuvanted 3.75microg HA vaccine group (traumatic brain injury) which was not considered as related to vaccination. In conclusion, these data suggest that a first dose of AS03(B)-adjuvanted A/H1N1/2009 vaccine containing 1.9microg HA in children 6-35 months old is highly immunogenic and that the overall reactogenicity profile is acceptable although reactions including fever tend to increase after a second dose.

Immunogenicity and safety of AS03-adjuvanted H1N1 pandemic vaccines in children and adolescents

Vaccines with acceptable efficacy profile against the H1N1 A/California/7/2009 virus are needed for use in children. The two studies presented here evaluated the immunogenicity and the reactogenicity/safety of A/H1N1/2009 vaccines containing either 3.75 μg haemagglutinin antigen (HA) and AS03(A)-adjuvant (3.75 μg HA/AS03(A) study) (N=210 [53, 57 and 100 in the 3-5, 6-9 and 10-17 years age strata, respectively]) or 1.9 μg HA and AS03(B)-adjuvant (1.9 μg HA/AS03(B) study) (N=244 [61, 65 and 118 in the 3-5, 6-9 and 10-17 years age strata, respectively]), given as two-dose series. Although the haemagglutination inhibition antibody titres were higher in the 3.75 μg HA/AS03(A) study, both vaccine dosages were highly immunogenic and exceeded regulatory acceptance criteria after the first and the second doses. Seroprotection rates reached 100% and seroconversion rates ranged from 98.2% to 99.1% after each dose of both vaccine dosages. Geometric mean titres increased from 456.5 to 1538.5 and from 297.9 to 1106.7 between the first and the second doses in the 3.75 μg HA/AS03(A) study and the 1.9 μg HA/AS03(B) study, respectively. Despite an observed slight increase of the reactogenicity following the second dose in the 3.75 μg HA/AS03(A) study, the vaccines safety profiles were considered clinically acceptable. In conclusion, both dosages of the AS03-adjuvanted A/H1N1/2009 pandemic influenza vaccines were highly immunogenic and well-tolerated in children and adolescents.

Assessment of the immunogenicity and reactogenicity of a quadrivalent diphtheria, tetanus, acellular pertussis and hepatitis B (DTPa-HBV) vaccine administered in a single injection with Haemophilus influenzae type b conjugate vaccine, to infants at 2, 4 and 6 months of age.

This double-blind, randomised study was performed to assess the immunogenicity and reactogenicity of three lots of a quadrivalent diphtheria-tetanus-acellular pertussis-hepatitis B vaccine (DTPa-HBV) co-administered with three lots of Haemophilus influenzae type b conjugate (Hib) vaccine in one injection, as a primary vaccination course in healthy infants at 2, 4 and 6 months of age. 269 infants (8-11 weeks of age) were randomly allocated to three groups to receive DTPa-HBV/Hib vaccines, concomitantly with oral polio vaccine. Blood samples for antibody determinations were taken before vaccination and 1 month after the third dose in 262 subjects. Local and general symptoms were recorded by parents on diary cards. All vaccinees had post-vaccination protective anti-D and anti-T (> or = 0.1 IU ml-1) antibodies, and 98% had protective anti-HBs antibody titres (> or = 10 mIU ml-1). There were no statistically significant differences between groups in post-vaccination anti-D, anti-T, anti-HBs antibody geometric mean titres (GMT), these being 3.49 IU ml-1, 5.92 IU ml-1 and 1109 mIU ml-1, respectively. All subjects responded to three pertussis components, i.e. pertussis toxin (PT), filamentous haemagglutinin (FHA) and pertactin (PRN). Although statistically significant differences in GMTs of anti-PT, anti-FHA and anti-PRN were found between groups, these were not believed to be of any clinical relevance as the minimum GMTs were 60, 193 and 230 EL.U ml-1 for anti-PT, anti-FHA and anti-PRN, respectively. There were no statistically significant differences in anti-PRP antibody GMT (4.05 micrograms ml-1) between groups, 100% and 85% of subjects having titres > or = 0.15 and 1.0 microgram ml-1, respectively. No symptoms were reported for one third of the subjects. Fever (> 38 degrees C) was reported after 16% of doses, with < 1% having > 39.5 degrees C. Almost all local and general symptoms were mild or moderate, and lasted less than 48 h. No subject dropped out due to a severe adverse reaction. The administration of an experimental mix of DTPa-HBV and Hib vaccines in a single injection is safe, well-tolerated and immunogenic for all vaccine components.

Newborn universal immunisation against hepatitis B: immunogenicity and reactogenicity of simultaneous administration of diphtheria/tetanus/pertussis (DTP) and oral polio vaccines with hepatitis B vaccine at 0, 2 and 6 months of age

The reactogenicity and immunogenicity of the administration of recombinant vaccine against hepatitis B simultaneously (but at separate sites) with diphtheria/tetanus/pertussis (DTP) and oral polio vaccines were examined. Six hundred and twenty-six children (group I) were given hepatitis B vaccine at 0, 2 and 6 months of age; the other vaccines were administered at 2, 4 and 6 months of age. A control group of 731 children (group II) received only DTP and oral polio vaccines. The results showed that 93% of the infants in group I had anti-HBs titres above the protective level ( > or = 10 mIU ml-1) after vaccination. There were no differences in the immune responses for DTP and polio between the two study groups. The vaccine efficacy against poliomyelitis was 96% for serotype I, 100% for serotype II and 97-98% for serotype III. Of the infants in both groups, 97% had antibodies against B. pertussis; all children were positive for tetanus and diphtheria. There were no differences in the incidences of general reactions between groups. Local swelling and redness were reported following 4.2 and 4.4%, respectively, of all injections of hepatitis B vaccine. These reactions were reported following 31 and 33%, respectively, of all doses of DTP vaccine. It can be concluded that the simultaneous administration of hepatitis B vaccine with the DTP and polio vaccines is well-tolerated; hepatitis B vaccine remained highly immunogenic and did not interfere with the immune response to the other antigens.

Safety and immunogenicity of an inactivated hepatitis A vaccine in children 2 to 5 years old

SummaryThe reactogenicity and immunogenicity of an inactivated hepatitis A vaccine were assessed. Seventy healthy children aged between 2 and 5 years old, who lacked antibodies against the hepatitis A virus, were enrolled in this study. With a 0-, 1-, and 6-month vaccination schedule, the children received three doses of 360 enzyme-linked immunosorbent assay (ELISA) units of hepatitis A vaccine intramuscularly (deltoid). Safety parameters were recorded in standardized diary cards by the parents on the day of injection and the three following days. Blood tests for liver enzymes and anti-hepatitis A virus antibody analyses were performed the day of screening and 1, 2, 6 and 7 months after the first dose. Anti-hepatitis A virus antibody was tested by ELISA. Titres < 20 mIU/ml were considered negative. For the three hepatitis A vaccine doses administered, 22% (46/210) of the diary cards reported any kinds of signs or symptoms. Soreness at the injection site (9%, 18/210) and malaise (6%, 12/210) were the most common local and systemic reactions reported, respectively. The seroconversion rates were 83, 99 and 100% one month after the 1st, 2nd, and 3rd doses, respectively. The corresponding geometric mean titres were 124, 352, and 2,778 mIU/ml. We conclude that this HAV vaccine is safe and immunogenic in healthy children. As the hepatitis A epidemiology pattern is rapidly changing in our country (and other regions), resulting in an increasing population of susceptible adolescents and young adults, we suggest that the routine vaccination against hepatitis A in pre-school children attending day-care centres should be seriously considered.ZusammenfassungEine inaktivierte Hepatitis A-Vakzine wurde auf ihre Verträglichkeit und Immunogenität untersucht. In die Studie wurden 70 gesunde Kinder ohne Antikörper gegen das Hepatitis A-Virus aufgenommen. Das Impfschema bestand aus der intramuskulären Gabe (M. deltoideus) von drei Dosen von 360 ELISA-Einheiten der Hepatitis A-Vakzine zum Zeitpunkt 0, 1 und 6 Monaten. Die Sicherheitsparameter wurden von den Eltern auf Tagebuchkarten am Tag der Injektion und an den drei folgenden Tagen dokumentiert. Am Tag des Screening, nach 1, 2, 6 und 7 Monaten wurden die Leberenzyme und anti-Hepatitis A Virus-Antikörper im Blut bestimmt. Die anti-Hepatitis A Virus-Antikörperbestimmung erfolgte mittels ELISA. Titer von 20 mIU/ml wurden als negativ eingestuft. Bei 22% (46/210) der in drei Dosen applizierten Impfungen fanden sich in den Aufzeichnungen auf den Tagebuchkarten keine Symptome oder Beschwerden. Die häufigsten lokalen und Allgemeinbeschwerden waren Schmerzen an der Injektionsstelle (9%; 18/20) und schlechtes Befinden (6%; 12/210). Einen Monat nach der ersten, zweiten und dritten Dosis lagen die Konversionsraten bei 83, 99 und 100%. Dabei fanden sich die entsprechenden Titer (geometrisches Mittel) von 124, 352 und 2 778 mIU/ml. Wir schließen aus den Ergebnissen, daß diese HAV-Vakzine bei gesunden Kindern sicher und immunogen ist. Da sich das epidemiologische Muster der Hepatitis A in unserem Land (und anderen Regionen) rasch ändert und ein immer größerer Anteil der Bevölkerung im Adoleszentenalter und frühen Erwachsenenalter empfänglich für die HAV Infektion ist, empfehlen wir die Routineimpfung gegen Hepatitis A bei Vorschulkindern, die in Tagesstätten untergebracht sind, ernsthaft zu erwägen.

A short in-frame deletion in NTRK1 tyrosine kinase domain caused by a novel splice site mutation in a patient with congenital insensitivity to pain with anhidrosis

BackgroundCongenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive genetic disease characterized by the lack of reaction to noxious stimuli and anhidrosis. It is caused by mutations in the NTRK1 gene, which encodes the high affinity tyrosine kinase receptor I for Neurotrophic Growth Factor (NGF).Case PresentationWe present the case of a female patient diagnosed with CIPA at the age of 8 months. The patient is currently 6 years old and her psychomotor development conforms to her age (RMN, SPECT and psychological study are in the range of normality). PCR amplification of DNA, followed by direct sequencing, was used to investigate the presence of NTRK1 gene mutations. Reverse transcriptase (RT)-PCR amplification of RNA, followed by cloning and sequencing of isolated RT-PCR products was used to characterize the effect of the mutations on NTRK1 mRNA splicing. The clinical diagnosis of CIPA was confirmed by the detection of two splice-site mutations in NTRK1, revealing that the patient was a compound heterozygote at this gene. One of these alterations, c.574+1G>A, is located at the splice donor site of intron 5. We also found a second mutation, c.2206-2 A>G, not previously reported in the literature, which is located at the splice acceptor site of intron 16. Each parent was confirmed to be a carrier for one of the mutations by DNA sequencing analysis. It has been proposed that the c.574+1G>A mutation would cause exon 5 skipping during NTRK1 mRNA splicing. We could confirm this prediction and, more importantly, we provide evidence that the novel c.2206-2A>G mutation also disrupts normal NTRK1 splicing, leading to the use of an alternative splice acceptor site within exon 17. As a consequence, this mutation would result in the production of a mutant NTRK1 protein with a seven aminoacid in-frame deletion in its tyrosine kinase domain.ConclusionsWe present the first description of a CIPA-associated NTRK1 mutation causing a short interstitial deletion in the tyrosine kinase domain of the receptor. The possible phenotypical implications of this mutation are discussed.

Economic and psychosocial impact of rotavirus infection in Spain: a literature review.

Severe rotavirus gastroenteritis is common in children under 5 years of age. A literature review was performed to investigate the economic and psychosocial impact of rotavirus infection in children in this age group. We retrieved 56 articles on the economic burden of the disease in Europe, 18 of them reported data from Spain; 8 articles were retrieved analysing its psychosocial impact. In Spain, rotavirus is responsible for 14% to 30% of all cases of gastroenteritis, and a quarter of these require hospitalisation. It is also associated with high use of health care resources (emergency and primary care visits). Rotavirus gastroenteritis costs the Spanish national health system EUR 28 million a year and causes productivity loss in two-thirds of parents (mean of 4 days). Taking into account these costs, it was estimated that implementing universal vaccination could prevent 76% to 95% of hospital admissions due to rotavirus gastroenteritis, as well as reduce emergency and paediatric visits, nosocomial infections, and days missed from work (77% reduction). Rotavirus gastroenteritis also has a considerable psychosocial impact on the family, although it is difficult to compare results due to the diversity of study designs and the low specificity of the measurement tools used. It also causes high stress among parents, adding to their workload and adversely affecting their quality of life.

Safety and persistence of the humoral and cellular immune responses induced by 2 doses of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine administered to infants, children and adolescents: Two open, uncontrolled studies

In children, 2 AS03-adjuvanted A(H1N1)pdm09 vaccine doses given 21 days apart were previously shown to induce a high humoral immune response and to have an acceptable safety profile up to 42 days following the first vaccination. Here, we analyzed the persistence data from 2 open-label studies, which assessed the safety, and humoral and cell-mediated immune responses induced by 2 doses of this vaccine. The first study was a phase II, randomized trial conducted in 104 children aged 6–35 months vaccinated with the A(H1N1)pdm09 vaccine containing 1.9 µg haemagglutinin antigen (HA) and AS03B (5.93 mg tocopherol) and the second study, a phase III, non-randomized trial conducted in 210 children and adolescents aged 3–17 years vaccinated with the A(H1N1)pdm09 vaccine containing 3.75 µg HA and AS03A (11.86 mg tocopherol). Approximately one year after the first dose, all children with available data were seropositive for haemagglutinin inhibition and neutralising antibody titres, but a decline in geometric mean antibody titres was noted. The vaccine induced a cell-mediated immune response in terms of antigen-specific CD4+ T-cells, which persisted up to one year post-vaccination. The vaccine did not raise any safety concern, though these trials were not designed to detect rare events. In conclusion, 2 doses of the AS03-adjuvanted A(H1N1)pdm09 vaccine at 2 different dosages had a clinically acceptable safety profile, and induced high and persistent humoral and cell-mediated immune responses in children aged 6–35 months and 3–17 years. These studies have been registered at www.clinicaltrials.gov NCT00971321 and NCT00964158.

A public-professional web-bridge for vaccines and vaccination: User concerns about vaccine safety

Vacunas.org (http://www.vacunas.org), a website founded by the Spanish Association of Vaccinology offers a personalized service called Ask the Expert, which answers any questions posed by the public or health professionals about vaccines and vaccination. The aim of this study was to analyze the factors associated with questions on vaccination safety and determine the characteristics of questioners and the type of question asked during the period 2008-2010. A total of 1341 questions were finally included in the analysis. Of those, 30% were related to vaccine safety. Questions about pregnant women had 5.01 higher odds of asking about safety (95% CI 2.82-8.93) than people not belonging to any risk group. Older questioners (>50 years) were less likely to ask about vaccine safety compared to younger questioners (OR: 0.44, 95% CI 0.25-0.76). Questions made after vaccination or related to influenza (including H1N1) or travel vaccines were also associated with a higher likelihood of asking about vaccine safety. These results identify risk groups (pregnant women), population groups (older people) and some vaccines (travel and influenza vaccines, including H1N1) where greater efforts to provide improved, more-tailored vaccine information in general and on the Internet are required.

Estudio prospectivo para estimar la carga de hospitalización y visitas a urgencias de la gripe en población pediátrica en Bilbao (2010-2011)

Resumen Introducción El estudio se llevó a cabo para estimar la carga de enfermedad de la gripe confirmada por laboratorio en niños menores de 15 años. Pacientes y métodos Los niños que acudieron al Hospital Universitario de Basurto con síntomas de infección respiratoria aguda y/o fiebre aislada entre noviembre de 2010 y mayo de 2011 fueron incluidos en el estudio (NCT01592799). Se tomaron 2muestras de secreción nasofaríngea: una para un test de diagnóstico rápido en el Servicio de Urgencias y otra para análisis en laboratorio con reacción en cadena de la polimerasa en tiempo real y cultivo viral. Resultados Se seleccionó a un total de 501 niños, de los que 91 fueron hospitalizados. El diagnóstico de gripe se confirmó en 131 (26,1%); 120/410 (29,3%) fueron tratados ambulatoriamente y 11/91 (12,1%), hospitalizados. En 370/501 niños (73,9%) el resultado no fue positivo. La proporción de otros virus respiratorios fue 145/501 (28,9%) casos y de coinfección con otro virus respiratorio además de gripe de 7/501 (1,4%). Los tipos de virus de gripe fueron: A (H1N1 y H3N2) 53,2% (67/126); B (Victoria y Yamagata) 46,0% (58/126); A+B 0,8% (1/126). El coste médico directo medio asociado con cada caso de gripe confirmada fue de 177,00€ (N=131). No se observaron diferencias estadísticamente significativas entre el coste asociado con gripe A o B. Conclusión Casi la mitad de los casos fueron virus de gripe B. La administración de una vacuna que incluya tipos A y B de gripe debería reducir la carga de la enfermedad. Abstract Introduction This study was undertaken to estimate the burden of morbidity associated with laboratory-confirmed influenza in children below 15 years of age. Patients and methods Children presenting with acute respiratory infection and/or isolated fever at the Basurto University Hospital, Bilbao, Spain between November 2010 and May 2011 were included in this study (NCT01592799). Two nasopharyngeal secretion samples were taken from each; one for a rapid influenza diagnostic test in the emergency department, and the second for laboratory analysis using real-time polymerase chain reaction and viral culture. Results A total of 501 children were recruited, of whom 91 were hospitalized. Influenza diagnosis was confirmed in 131 children (26.1%); 120 of 410 (29.3%) treated as outpatients and 11 of 91 (12.1%) hospitalized children. A total of 370 of 501 children (73.9%) had no laboratory test positive for influenza. The proportion of subjects with other respiratory viruses was 145/501 (28.9%) cases and co-infection with the influenza virus plus another respiratory virus was detected in 7/501 (1.4%) cases. Influenza virus types were: A (H1N1 and H3N2) 53.2% (67/126); B (Victoria and Yamagata) 46.0% (58/126); A+B 0.8% (1/126). The median direct medical costs associated with each case of laboratory-confirmed influenza was €177.00 (N=131). No significant differences were observed between the medical costs associated with influenza A and B. Conclusion Almost half of the cases were influenza virus B type. The administration of a vaccine containing influenza A and B types to children below 15 years of age might reduce the overall burden of the illness.