Pirmin Habermehl

Immunogenicity and safety of two doses of tetravalent measles-mumps-rubella-varicella vaccine in healthy children.

Background: Combination vaccines against common childhood diseases are widely used, provide an improved coverage, are more convenient and are more cost-effective than multiple injections. We conducted a study to evaluate the safety and immunogenicity of acombined measles-mumps-rubella-varicella (MMRV) candidate vaccine in comparison with the separate administration of licensed measles-mumps-rubella (MMR; Priorix) and varicella (V; Varilrix) vaccines. Methods: Healthy children 12–18 months of age received 2 doses of MMRV vaccine (3 lots) 6–8 weeks apart (MMRV group) or 1 dose of MMR vaccine administered concomitantly with 1 dose of varicella vaccine, followed by a second dose of MMR at 6–8 weeks later (MMR+V group). Local symptoms (redness, pain and swelling) were recorded for 4 days after vaccination, and fever (any, axillary temperature ≥37.5°C or rectal temperature ≥38.0°C; grade 3, axillary temperature >39.0°C or rectal temperature >39.5°C) was monitored daily for 15 days. Other adverse events were monitored for 6 weeks. Results: A total of 494 children were vaccinated (371 in the MMRV group and 123 in the MMR+V group. Two doses of MMRV vaccine were at least as immunogenic as 2 doses of MMR and 1 dose of varicella vaccine. After the second dose, all children had seroconverted to measles, rubella and varicella in both vaccine groups, and 98% versus 99% had seroconverted to mumps in the MMRV versus the MMR+V group, respectively. The MMRV vaccine did not induce an increased local or general reactogenicity compared with the separate administration, although a higher incidence of low grade fever was seen after the first dose in the MMRV group (67.7% after MMRV versus 48.8% after MMR+V; P < 0.05), this was not observed for grade 3 fever (11.6% after MMRV versus 10.6% after MMR+V; P = 0.87). After the second dose, no differences in incidence of fever were found in either MMRV or MMR+V groups. Conclusion: Administration of 2 doses of the combined MMRV vaccine was as immunogenic and well-tolerated as separate injections of MMR and varicella vaccine.

Immunogenicity, reactogenicity, and immune memory after primary vaccination with a novel Haemophilus influenzae-Neisseria meningitidis serogroup C conjugate vaccine.

ABSTRACT We evaluated two formulations of a new combined Haemophilus influenzae type b (Hib)-meningococcal serogroup C (MenC)-tetanus toxoid (TT) conjugated vaccine and two formulations of a new MenC-TT vaccine (trials 711202/001 and 711202/008; clinical trial register numbers NCT00135486 and NCT00135564 [www.ClinicalTrials.gov ]). A total of 520 healthy infants were randomized to receive primary vaccination (at 2, 3, and 4 months) with either MenC-TT plus diphtheria-tetanus-acellular pertussis (DTPa)-hepatitis B virus (HBV)-inactivated poliovirus (IPV)/Hib, Hib-MenC-TT plus DTPa-HBV-IPV, or MenC-CRM197 plus DTPa-HBV-IPV/Hib (control). At 12 to 15 months, subjects received a polysaccharide challenge with meningococcal polysaccharide C plus a DTPa-HBV-IPV/Hib booster. Immune responses were assessed 1 month after dose 2, 1 month after dose 3, and prior to and 1 month after the booster. After primary vaccination, there was no difference between groups in seroprotection rates as measured by titers of serum bactericidal antibody (SBA) to MenC (≥1:8) or concentrations of anti-polyribosyl ribitol phosphate (PRP) antibody (≥0.15 μg/ml). Prior to the booster, there was no difference between groups in SBA seroprotection rates, whereas anti-PRP seroprotection rates were significantly higher after priming with Hib-MenC-TT. Booster doses induced large increases in SBA and anti-PRP antibodies in primed groups, indicating successful priming with induction of immune memory. Reactogenicity and safety were similar in all groups during the primary and booster phases. A novel combined Hib-MenC-TT conjugate vaccine induced MenC and Hib responses comparable to those induced by licensed monovalent vaccines. A Hib-MenC-TT conjugate vaccine provides vaccination against two major pathogens in a single injection and is a suitable candidate for use in primary or booster vaccination schedules.

Age-Dependent Association of Human Mannose-Binding Lectin Mutations With Susceptibility to Invasive Meningococcal Disease in Childhood

Background: Mannose-binding lectin (MBL) is an important factor of the innate immune system, and MBL-initiated complement activation is an important early defense mechanism against various bacterial infections, including invasive meningococcal disease. Methods: In a pediatric cohort (ages 2–215 months) with invasive meningococcal disease, we investigated the overall and age-stratified frequency of 3 MBL exon 1 variations (C154T, G161A, G170A), previously shown to result in markedly decreased MBL plasma concentrations, by allele specific fluorescent hybridization probe real-time PCR assays and direct sequencing. Healthy age-matched volunteers with the same ethnic background and no history of meningococcal disease served as a control group. Results: The overall frequency of a MBL exon 1 variant genotype was significantly higher in patients than in controls (31.8% vs. 8.2%, P < 0.001). In the patient group with disease onset less than 24 months of age, the prevalence of MBL structural variant genotype was further increased (39.3%; P < 0.001) and most pronounced in children with disease onset less than 12 months of age (57.1%; P < 0.001) when compared with healthy controls. Analysis of clinical severity and outcome revealed no significant difference between patients with wild-type and mutant alleles. Conclusions: Our data suggest that MBL exon 1 structural variants are significantly associated with susceptibility to childhood meningococcal disease in an age-dependent manner.

Linking C5 Deficiency to an Exonic Splicing Enhancer Mutation

As an important component of the innate immune system, complement provides the initial response to prevent infections by pathogenic microorganisms. Patients with dysfunction of C5 display a propensity for severe recurrent infections. In this study, we present a patient with C5 deficiency demonstrated by immunochemical and functional analyses. Direct sequencing of all C5 exons displayed no mutation of obvious functional significance, except for an A to G transition in exon 10 predicting an exchange from lysine to arginine. This sequence alteration was present in only one allele of family members with a reduced serum C5 concentration and in both alleles of the patient with almost complete C5 deficiency, suggesting that this alteration may be producing the phenotype. Recent findings indicate that distinct nucleotide sequences, termed exonic splicing enhancers (ESEs), influence the splicing process. cDNA from all family members harboring the mutated allele showed skipping of exon 10, which resulted in a premature STOP codon, explaining the lack of C5 in the propositus. Sequence analysis of the mutated region revealed the substitution to be located within an ESE, as predicted by the RESCUE-ESE program. The altered ESE sequence is located close to the 5′ splicing site and also lowers the predicted strength of the splice site itself. This apparently inconsequential sequence alteration represents a noncanonical splicing mutation altering an ESE. Our finding sheds a new light on the role of putative silent/conservative mutations in disease-associated genes.

Immunogenicity and reactogenicity of acellular pertussis booster vaccines in children Standard pediatric versus a reduced-antigen content formulation

Booster vaccination with a reduced-antigen-content dTpa, pediatric DTPa or adult Td vaccine in DTPa-primed children aged 4-6 years was evaluated. Immunogenicity and CMI was assessed one month and 3.5 years after vaccination. Symptoms were solicited for 15 days post-vaccination. There were no differences between groups in diphtheria or tetanus seroprotection or pertussis vaccine-response rates. Anti-diphtheria and anti-PRN concentrations were higher after DTPa, but groups differences reduced over time. Non-significant trends toward reduced reactogenicity of dTpa were observed. Many factors influence vaccine choice at pre-school age. The dTpa vaccine was as immunogenic and possibly better tolerated than DTPa at this age.

Changes in lymphocyte subsets after cardiac surgery in children.

Abstract. Children undergoing cardiopulmonary bypass (CPB) operations have an increased risk of developing severe infections. Impairment of the immune system may contribute to the development of sequelae such as capillary leaks, pulmonary dysfunction and auto-immune reactions. The objective of this study was to investigate the impact of cardiac surgery with CPB on the immune system of infants and young children. We conducted a prospective study to investigate the changes in circulating lymphocyte subpopulations in a sample of 21 consecutive infants and young children undergoing cardiac surgery for congenital heart disease. The following statistically significant (P<0.05) results were obtained: leucocyte counts rose 6 h after surgery due to the increase in neutrophils. Absolute T-cell number and absolute T-helper cell number decreased within 24 h after CPB. The proportion of T-cells expressing the T-cell receptor γδ as well as natural killer cells increased during CPB. In contrast, the proportion of T-cells expressing activation markers (CD25, CD45R0) decreased within 24 h after CPB, as did the number of cells expressing adhesion molecules (CD11b and ICAM). Conclusion: during cardiac surgery with cardiopulmonary bypass, absolute natural killer cell counts increase while T-cells decrease, presumably due to an extravasation or adhesion of activated T-cells. The relevance of this finding regarding the risk of infection is discussed.

Safety and efficacy of interferon retreatment in children with chronic hepatitis B

More than 50% of children with chronic hepatitis B do not respond to treatment with alpha-interferon. Since these patients continue to display high viral replication and progressive liver disease, retreatment should be considered. To date it has not been well evaluated whether a second course of treatment could increase the response rate. In two alpha-interferon retreatment trials in adult patients the response rate, defined by seroconversion from HBeAg to anti-HBe, ranged between 11% and 44%. One beta-interferon retreatment study in children reported a seroconversion rate of 32%. Regrettably, none of the studies included a control group observing the ‘spontaneous’ seroconversion rate after a first interferon cycle. Thus, a nonrandomized alpha-interferon retreatment study in children including control patients was performed. Alpha-interferon for retreatment was administered 3 times a week for 16–24 weeks in 15 children (5–16 years) at least 6 months after ceasing the first cycle. Four children received 5 MU/m2 of a natural alpha-interferon and 11 children 9 MU/m2 recombinant alpha-interferon 2b. Follow up was 18–47 months after initial treatment. In parallel, a control group of 19 un-retreated children with comparable clinical and demographic data was followed for 12–39 months. HBeAg seroconversion was observed in 5 (33%) of the retreated children and in 5 (26%) of the control patients during follow up. The difference is not significant. In the initially nonresponding children, those with high ALT levels before the first treatment showed late HBeAg seroconversion more frequently than those with low ALT levels (P = 0.017) irrespective of retreatment. The ALT level before retreatment was not a predictor for response.ConclusionsA second cycle of alpha-interferon during the 3 years following the first treatment in nonresponding children with chronic hepatitis B can be safely performed but did not increase HBeAg/anti-HBe seroconversion compared with the spontaneous seroconversion rate of patients without retreatment.

Cellular immune response of a varicella vaccine following simultaneous DTaP and VZV vaccination

BACKGROUND Chickenpox and zoster are an important cause of morbidity among children and adults. The ability of a new, thermostable vaccine to induce varicella-zoster-virus (VZV)-specific humoral and cell mediated immunity when given simultaneously with diphtheria-tetanus-acellular pertussis vaccine (DTaP) as a booster dose in the second year of life was investigated. METHODS A new, temperature stable varicella vaccine (OKA-strain, SB-Biologicals, Rixensart, Belgium) was given simultaneously with a booster dose of DTaP vaccine. VZV-specific humoral and cell-mediated immunity was studied in the first 27 out of 232 vaccinated children at 16-28 months of age, from blood samples drawn just before and six weeks after vaccination. VZV-specific antibody response, T-cell proliferation, cytokine production and expression of activation markers (CD25, HLADR) on T-cells were analyzed. RESULTS Vaccination resulted in a significant rise of VZV-specific serum IgG titers and in a strong VZV-specific T-cell response in all vaccinated infants. Analysis of the expression of activation marker revealed activation of both CD4+-T-helper- and CD8+-T-cells. CONCLUSIONS The varicella vaccine given simultaneously with DTaP produced strong B- and T-cell responses alike. This is the first report to show that CMI to VZV is conferred to young children by vaccination with a temperature stable VZV vaccine.

Distribution of lymphocyte surface antigens in healthy neonates

Using flow cytometric analysis we investigated the distribution of major lymphocyte surface antigens in newborn infants. A total of 221 newborns entered the study, of whom 53 fullfilled our criteria of healthy mature neonates. Percentages of immunofluorescent-positive cells were as follows (median and range from 25th to 75th percentiles given): for CD1 3.8%; 2.3%–5.8%. CD2 60.9%; 52.4%–66.8%. CD3 57.5%; 50.5%–63.3%. TcRaß 57.7%; 48.1%–60.0%. CD4 36.3%; 28.0%–42.6%. CD8 23.0%; 20.0%–27.4%. CD11a 56.3%; 46.3%–68.5%. CD19 12.1%; 8.6%–14.8%. CD20 10.9%; 8.4%–12.9%. CD25 2.6%; 2.1%–4.5%. CDw52 61.0%; 51.2%–76.1%. CD71 5.2%; 3.1%–9.3%. While the ranges for the percentage of immunofluorescent-positive cells were rather small, there was a wide variation in the absolute numbers of marker immunofluorescent-positive cells.

Varizellen und Varizellenimpfung

ZusammenfassungMit etwa 750.000 Krankheitsfällen pro Jahr in Deutschland—die Mehrzahl davon sind Kinder—stellen Windpocken die häufigste durch Schutzimpfung zu verhindernde Infektionskrankheit dar. Schätzungen zufolge kommt es dabei zu bis zu 40.000 Komplikationen bei Kindern und Erwachsenen. Als Komplikationen treten vor allem bakterielle Superinfektionen, Otitis media, Pneumonien und Bronchitiden auf, aber auch neurologische Komplikationen wie Zerebellitis, Meningitis und Enzephalitis kommen vor. Das höchste Risiko für Komplikationen haben zum einen Erwachsene, zum anderen aber auch Kinder im ersten Lebensjahr. Infolge der hohen Fallzahlen sowie der zahlreichen Komplikationen bedeuten Varizellen eine erhebliche ökonomische Belastung für die deutsche Volkswirtschaft. Bei einer generellen Impfung aller Kleinkinder gegen Windpocken ist also mit einem starken Rückgang der Morbidität sowie mit Kosteneinsparungen in Millionenhöhe zu rechnen. Die Erfahrungen aus den USA, wo seit fast acht Jahren alle Kinder gegen Windpocken geimpft werden, belegen die gute Verträglichkeit und Wirksamkeit der Impfung. Erste Studien ergaben einen Rückgang der Fallzahlen um 71–84%, bei Impfraten von mehr als 80% für Kinder bis drei Jahre im Jahr 2002. Außerdem ist in den USA eine Abnahme der Windpocken-Inzidenz auch bei Ungeimpften zu verzeichnen, eine Folge der einsetzenden Herdimmunität. Prinzipiell ist daher eine generelle Impfempfehlung für Varizellen in Deutschland gut begründbar. Offene Fragen betreffen vor allem eine mögliche Altersverschiebung der Varizellen in geimpften Populationen sowie den Einfluss der Varizellenimpfung auf die Zosterinzidenz bei Erwachsenen.AbstractConsidering about 750.000 cases of chickenpox each year in Germany—most of these cases occur in children—varicella is the most frequent infectious disease preventable by vaccination. It is estimated that up to 40.000 complications from chickenpox occur annually in adults and children. Complications of varicella include mainly bacterial superinfection, otitis media, pneumonia and bronchitis, but cerebelitis, meningitis and encephalitis also occur. Adults and children in their first year of life are at the highest risk for complications. The large numbers of cases and complications clearly show that varicella has a high impact on the German national economy. Universal mass vaccination against chickenpox in Germany is expected to significantly reduce the morbidity and yield savings in overall healthcare costs amounting to several million Euros. There has been a general varicella vaccination recommendation for the last 8 years in the USA, which confirms the safety and high efficacy of the vaccine. Preliminary studies show a reduction of chickenpox cases in the USA by 71–84% and vaccine coverage rates for children under the age of 3 years of more than 80% in 2002. Due to the ensuing herd immunity in the USA, a reduction in the number of chickenpox cases in unvaccinated persons has been seen, too. In principle a general varicella vaccination in Germany is well-founded. Still matters of concern are a possible age-shift in vaccinated populations as well as the influence of routine varicella vaccination on zoster incidence in adults.