Effectiveness of the DTPa-HBV-IPV/Hib vaccine against invasive Haemophilus influenzae type b disease in the Netherlands (2003-16): a case-control study

Lancet Infect Dis. 2018 Jul;18(7):749-757. doi: 10.1016/S1473-3099(18)30166-X. Epub 2018 May 8.


Background: In 2016, an increase in invasive Haemophilus influenzae serotype b (Hib) disease was reported in the Netherlands in children younger than 5 years, which coincided with the introduction of the hexavalent diphtheria, tetanus, and acellular pertussis-hepatitis B virus-inactivated polio virus/Hib vaccine (DTPa-HBV-IPV/Hib) from 2011 onwards. We aimed to estimate the effectiveness of the hexavalent vaccine to assess whether this increase could be explained by decreasing effectiveness.

Methods: We did a case-control study in the Netherlands. We selected patients with a Hib infection (cases) by use of the surveillance records of the Netherlands Reference Laboratory for Bacterial Meningitis (Amsterdam). Cases with a Hib infection that began from Jan 1, 2003, to Dec 31, 2016, and who were younger than age 5 years were included. Ten controls from the national vaccination register (Praeventis) were selected for each case, matched by date of birth. Vaccination status was ascertained by use of Praeventis, which details the vaccination records of children living in the Netherlands. The last recorded vaccine dose was used to classify the child as having received the hexavalent DTPa-HBV-IPV/Hib vaccine or a pentavalent vaccine (which excludes the hepatitis B virus component) or another vaccine. We estimated the effectiveness of these vaccines by use of conditional logistic regression.

Findings: We included 159 (94%) of 170 cases reported and 1590 matched controls, who had a median age of 1·5 years (IQR 0·8-2·9). The remaining 11 cases could not be cross-matched with vaccination records from Praeventis. 91 (57%) of 159 cases had been vaccinated, compared with 1408 (89%) of 1590 controls. The overall vaccine effectiveness was 92·8% (95% CI 88·7-95·4), with no differences between the year of disease onset (p=0·9670). There were no differences conferred by type of vaccine given: vaccine effectiveness of the pentavalent and other vaccines was 91·8% (95% CI 86·1-95·1) versus 94·0% (89·0-96·8) for the hexavalent vaccine (OR 0·72, 95% CI 0·36-1·45; p=0·3591). Vaccine effectiveness was highest in children aged 1-2 years at disease onset (97·1-99·0%) and was lowest in children aged 3-4 years at disease onset (60·7-82·3%; p=0·0008).

Interpretation: Our results support the current vaccination programme, since Hib vaccine effectiveness has not decreased over time or by the introduction of the hexavalent DTPa-HBV-IPV/Hib vaccine. Vaccine effectiveness was high but waned with age. Alternative explanations for the increase in Hib disease therefore need to be assessed.

Funding: Dutch Ministry of Health, Welfare and Sports.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Child, Preschool
  • Diphtheria / drug therapy*
  • Diphtheria / prevention & control
  • Diphtheria-Tetanus-Pertussis Vaccine / therapeutic use*
  • Female
  • Haemophilus Infections / drug therapy*
  • Haemophilus Infections / prevention & control
  • Haemophilus Vaccines / therapeutic use*
  • Haemophilus influenzae type b / drug effects*
  • Hepatitis B Vaccines / therapeutic use*
  • Humans
  • Immunization Schedule
  • Infant
  • Infant, Newborn
  • Male
  • Netherlands
  • Poliovirus Vaccine, Inactivated / therapeutic use*
  • Tetanus / drug therapy*
  • Tetanus / prevention & control
  • Vaccines, Combined / therapeutic use


  • DTPa-HBV-IPV combined vaccine
  • Diphtheria-Tetanus-Pertussis Vaccine
  • Haemophilus Vaccines
  • Hepatitis B Vaccines
  • Poliovirus Vaccine, Inactivated
  • Vaccines, Combined