Background: Following the introduction of conjugate vaccines against invasive Haemophilus influenzae type b (Hib) disease in Germany, the incidence of Hib disease dramatically decreased. Hib conjugate vaccines were combined with diphtheria, tetanus and acellular pertussis antigens (DTaP/Hib) and gradually replaced by higher-valent vaccines, additionally incorporating inactivated polio virus and - since the end of 2000 - hepatitis B (DTaP-IPV-HB/Hib or hexavalent vaccines). Recently, an increasing incidence of invasive Hib disease in children and an increasing number of vaccine failures have been reported from some European countries, which coincided with the introduction of combination vaccines containing the acellular pertussis component. Previous data in Germany showed no such increase and vaccine effectiveness (VE) of DTaP/Hib and DTaP-IPV/Hib combination vaccines against invasive Hib disease was estimated to be high. Since Germany is the first country who introduced hexavalent vaccines, insufficient data on the impact of hexavalent vaccines on invasive Hib disease and on the VE against invasive Hib disease in children exist.

Aim: To assess (1) annual numbers of Hib cases and vaccine failures of Hib vaccines before and after the introduction of hexavalent vaccines in German children, (2) annual incidences of invasive Hib disease before and after the introduction of hexavalent vaccines in German children and to estimate (3) VE of hexavalent vaccines against invasive Hib disease in German children.

Subjects and Methods: Invasive Haemophilus influenzae (Hi) infections in children less than 10 years were ascertained from 1998 to 2004 through two independent nation-wide active surveillance systems, one hospital- and one laboratory-based. Species confirmation and capsular testing was performed in the national consulting laboratory for Hi. Cases were defined by any hospitalisation due to a systemic infection clinically compatible with an invasive Hi disease and with isolation of Hi from a normally sterile body site. Annual case numbers and incidences were adjusted for underreporting and for differences in the proportion of typed cases over time. VE was determined with a case-cohort approach using Cox regression with time-dependent covariates. In this analysis, Hib cases born between August 2000 and June 2003, aged 2 months or older and ascertained from August 2000 to December 2003 were included for case-cohort analysis and a ‘sub’-cohort of children born in the same time frame as the cases was randomly sampled in a nationwide immunisation survey. Children receiving two/three Hib doses (depending on vaccine type) in the first year of life, without booster, were defined as ‘fully primed’, children receiving a single dose in the second year of life, regardless of priming, as receiving a ‘2nd year dose’ and children receiving a booster dose at the age of 11 months or later following full priming as receiving the ‘full immunisation’.

Results: In the two surveillance systems annual response rates since 1998 were >90%, the proportion of untyped Hi cases decreased from 25% of all reported cases in 1998 to 15% in 2004 and the proportion typed in the national consulting laboratory increased from 55% of all reported cases in 1998 to 70% in 2004. The annual number of Hi cases decreased from 51 in 1998 to 27 cases in 2004. Hib cases fluctuated between 28 in 1998 and 4 in 2004. Of all 117 Hib cases detected since 1998, 64 were not vaccinated and 52 were vaccinated at least once. 92% of the unvaccinated Hib cases and 53% of the vaccinated Hib cases could have received at least one (additional) dose if timing of general recommendations would have been followed. Of all vaccinated Hib cases, 12 had been vaccinated with at least one dose of a hexavalent vaccine. Overall annual incidence rates of Hi disease were relatively constant throughout the years 1998 through 2004 (0.8-0.4/100,000). Annual incidences of Hib disease ranged between 0.3 and