Ulrich Heininger

A search for serologic correlates of immunity to Bordetella pertussis cough illnesses.

In a pertussis vaccine efficacy trial in Germany we collected sera from vaccinees (DTaP or DTP) after the third and fourth doses of vaccine or at comparable time periods in DT vaccine recipients. In addition, sera were collected from a randomized sample of subjects in each vaccine group at approximately 3-month intervals from which antibody kinetic curves were constructed, which allowed us to estimate specific antibody values to pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin and fimbriae-2 at the time of exposure in the household setting. The imputed geometric mean antibody values to PT, pertactin and fimbriae-2 at the time of household exposure to Bordetella pertussis infection were higher (p < 0.07 or lower) in non-cases compared with cases. A multivariate (classification tree) analysis found that only pertactin and PT were significant in protection. Subjects with an imputed pertactin value of < 7 EU ml-1 had a 67% (18/27) chance of infection regardless of the PT value. If the pertactin value was > or = 7 EU ml-1 and the PT value > or = 66 EU ml-1 all subjects were non-cases. If the pertactin value was > or = 7 and the PT value was < 66 EU ml-1 the predicted probability of being a case was 31% (15/49). Logistic regression analysis also found that high versus low pertactin values were associated with illness prevention following household exposure. In the presence of antibody to pertactin, PT and fimbriae-2, the additional presence of antibody to FHA did not contribute to protection. Our data support historical data indicating that agglutinating antibodies are associated with protection and also recent serologic correlates data and clinical efficacy data which indicate that multicomponent vaccines containing pertactin and fimbriae have better efficacy than PT or PT/FHA vaccines.

Comparison of immunogenicity and reactogenicity of a measles, mumps and rubella (MMR) vaccine in German children vaccinated at 9-11, 12-14 or 15-17 months of age.

Children aged 9-11, 12-14 or 15-17 months, respectively were vaccinated with a measles, mumps and rubella (MMR) vaccine and serum antibody responses and reactogenicity were compared. The data of 118 children could be analysed (group 1=9-11 months, n=46; group 2=12-14 months, n=29, group 3, 15-17 months, n=43). The only significant difference observed was for seroconversion against measles virus between group 1 and group 3 (84.8% vs 100%, p=0.012). No serious adverse events were reported. Local side reactions were mild, infrequent and independent of age. Immunisation against MMR is safe and effective even when administered before the currently recommended age of 12 months.

Humoral immunity against diphtheria, tetanus and poliomyelitis after antineoplastic therapy in children and adolescents : a retrospective analysis

Serum antibodies against diphtheria- and tetanus-toxin were measured in 71 children and against poliomyelitis viruses 1-3 in 65 children and adolescents 0-18 months after cessation of antineoplastic therapy. Non or marginally protective serum titers were found in 62% of patients against diphtheria, in 18% of patients against tetanus and in 72% of patients against one or more poliomyelitis virus serotypes. Of these patients, 55%, 46% and 75% were immunized adequately according to age against diphtheria, tetanus and poliomyelitis, respectively. In 50% or more of patients a lack of protective immunity against diphtheria, tetanus and poliomyelitis was found which could not be explained by an inadequate immunization status. This suggests that other factors (e.g. influence of underlying illness, antineoplastic therapy or both on lymphocytes) might be responsible for these findings and this deserves further investigation. Measurement of serum antibodies against vaccine-preventable illnesses and consecutive booster immunizations are an essential part of long-term follow up in pediatric patients after antineoplastic therapy.

The Effect of Investigator Compliance (Observer Bias) on Calculated Efficacy in a Pertussis Vaccine Trial

Background. In the course of a large pertussis vaccine efficacy trial we realized that investigator compliance could have a major impact on calculated vaccine efficacy. Design. In our pertussis vaccine efficacy trial, the study investigators were to monitor illness in study families by telephone every 2 weeks. If a cough illness of ≥7 days duration was noted, the study child was to be evaluated. If the cough illness persisted for ≥14 days, the child was to be referred to a central investigator. For this report we analyzed study physician evaluation rates and rates of referral to the central investigators. Physician practices were separated into three compliance categories: high, intermediate, and low. We analyzed vaccine efficacy of an acellular pertussis component DTP vaccine (DTaP) and a whole cell pertussis component DTP vaccine (DTP) by compliance category. Bordetella pertussisinfection was documented by culture of the organism in the study child or in a household contact or by a significant antibody response to pertussis toxin determined by enzyme-linked immunosorbent assay. Results. Using a clinical case definition that included both mild and typical pertussis (cough illness ≥7 days duration) efficacy of DTaP vaccine was 40% (95% confidence interval [CI] = −3–65) in the high compliance category and 78% (95% CI = 65–86) and 75% (95% CI = 53–87) in the intermediate and low compliance groups, respectively. Similar, but less marked, differences in efficacy were noted with DTP vaccine recipients. Using a clinical case definition that required ≥21 days of cough with paroxysms, whoop, or vomiting (typical pertussis) the efficacy of DTaP vaccine was 69% (95% CI = 41–83) in the high compliance category and 86% (95% CI = 76–92) and 84% (95% CI = 64–93) in the intermediate and low compliance groups, respectively. In contrast, the efficacy of DTP vaccine did not vary by compliance category using this case definition. The attack rate in children vaccinated with diphtheria and tetanus toxoids vaccine (DT) was twofold less in low compliance physician practices when compared with the rates in high and intermediate groups. The DT/DTaP and DT/DTP fold-change differences were less in the high compliance group compared with the intermediate and low compliance groups. Conclusions. Our data suggest that observer compliance (observer bias), can significantly inflate calculated vaccine efficacy. It is likely that all recently completed efficacy trials have been effected by this type of observer bias and all vaccines have considerably less efficacy against mild disease than published data suggest.

Immunogenicity and reactogenicity of a single dose of a diphtheria–tetanus–acellular pertussis component vaccine (DTaP) compared to a diphtheria–tetanus toxoid (Td) and a diphtheria toxoid vaccine (d) in adults☆

We compared immunogenicity and reactogenicity of a single dose of DTaP vaccine (containing tetanus and diphtheria toxoids and four acellular pertussis antigens) with conventional Td- or d-vaccines in 180 German adults. Antibody values against diphtheria and tetanus toxin and against the pertussis antigens fimbriae (FIM), filamentous hemagglutinin (FHA) and pertussis toxin (PT) were measured in pre- and post-immunization sera. Reactogenicity was determined by a patient diary card. Pre-immunization antibody values against diphtheria toxin were low in all three vaccine groups. After immunization, > or = 80% of the vaccinees in all three groups were fully protected (> or = 0.1 IU/ml), but geometric mean values were significantly higher in DTaP recipients compared to Td or d recipients (1.65 vs. 0.44 and 0.48, respectively; both P < 0.05). Pre-immunization antibody values against tetanus toxin were high in all three groups, and after immunization 100% of the vaccinees were protected (> or = 0.1 IU/ml). Furthermore, substantial antibody responses against pertussis antigens were elicited in DTaP recipients with geometric mean rises of 22.5, 4.1 and 7.5 for antibodies against FHA, fimbriae and PT, respectively. All three vaccines were well tolerated. Frequency and severity of local reactions were similar between DTaP and Td recipients and even less common in d recipients. Since DTaP did provide a significant boost of anti-pertussis antibodies and a significantly higher anti-diphtheria response than conventional Td vaccine without an increase of side effects, it might be an appropriate candidate for use in adults.

Inzidenz und Symptomatik von hospitalisierten Gastroenteritiden in einer Kohorte von 10.271 Säuglingen und Kleinkindern

ZusammenfassungFragestellung: Eine prospektive Pertussisimpfstudie mit engmaschiger Überwachung des gesamten Kollektivs erlaubte uns, erstmals das Risiko von Säuglingen und Kleinkindern, wegen einer Gastroenteritis hospitalisiert zu werden, in einer umfangreichen Kohorte zu bestimmen.nn Methode: Die Kohorte aus 10.271 gesunden Kindern wurde, beginnend im Alter von 2–4 Monaten, über einen mittleren Zeitraum von 2,5 Jahren beobachtet (Gesamtbeobachtungsdauer 25.284 Jahre). Dabei wurden u.a. alle Krankenhausbehandlungen erfaßt.nn Ergebnisse: Bei 173 Kindern (1,7%) registrierten wir insgesamt 179 Gastroenteritisepisoden, die stationär behandelt wurden. Dies entspricht einer mittleren Inzidenz von 7,1/1000 Beobachtungsjahren mit einem Maximum von 11,2/1000 im 7. bis 12. Lebensmonat und einer Abnahme mit steigendem Lebensalter. Die beiden am häufigsten nachgewiesenen Erreger waren Rotaviren (34%) und Salmonellen (20%). Rotavirus-Infektionen traten gehäuft in der kalten Jahreszeit auf, die höchste Inzidenz lag bei Säuglingen im 7. bis 12. Lebensmonat. Die Symptomatik war geprägt von Enteritis (90%), Erbrechen (85%) und Zeichen der Dehydratation (58%). Demgegenüber trat der Großteil aller Salmonellosen in den Monaten Juli-September auf, mit einem Altersgipfel im 19. bis 24. Lebensmonat, charakterisiert durch Enteritis (92%), hohes Fieber (56%, >39°C) und erhöhte Werte des C-reaktiven Proteins (68%). Bei 5% bzw. 12% der wegen Rotavirus- bzw. Salmonelleninfektionen hospitalisierten Kinder war ein Fieberkrampf Anlaß für die Klinikeinweisung.nn Schlußfolgerung: Gastroenteritiden führen bei primär gesunden Kindern in den ersten Lebensjahren häufig zu Krankenhausbehandlungen. Rotaviren und Salmonellen sind dabei die prädominierenden Erreger.SummaryObjective: A pertussis vaccine efficacy trial included a prospective follow up of all hospitalizations involved. This allowed us to calculate the rates of hospitalization due to acute gastroenteritis in a large cohort of infants and children in Germany.nn Methods: 10271 healthy children were enrolled at the age of 2–4 months and followed up for a mean of 2.5 years. All hospitalizations during follow-up of the study were registered and letters of discharge from hospital in children with gastroenteritis were evaluated for the present analysis.nn Results: A total of 179 episodes of hospitalization due to a gastroenteritis were reported in 173 children (total observation years 25284). The mean calculated incidence was 7.1/1000 observation years, with a maximum of 11.2/1000 years in 7–12 month old children. Rotavirus and Salmonella spp. were the most frequently identified agents. Rotavirus infections were most prevalent during the cold season and the maximum incidence was between 7 and 12 months of age. Characteristic symptoms of rotavirus infections were diarrhea (90%), vomiting (85%) and signs of dehydration (58%). In contrast most Salmonella infections occurred between July and September with a peak between 19 and 24 months of age. Salmonella infections were characterized by enteritis (92%), high fever (56% >39°C) and significantly increased values for the c-reactive protein (68%). In this study rotavirus and Salmonella infections leading to hospitalization were associated with febrile seizures in 5% and 12% of cases, respectively.nn Conclusion: Gastroenteritis frequently leads to hospitalization in previously healthy infants and young children. Rotavirus and Salmonella spp. are the predominant causative agents.