Randomized Study of Not Giving Diphteria-tetanus-pertussis Vaccination With or After Measles Vaccination
Condition: Mortality; Hospitalization; Adverse Events
MeSH terms: Diphtheria
Study type: Interventional
Phase: Phase 4

Summary: 
      In non-randomized studies, routine childhood vaccinations have been observed to have
      non-targeted effects. Difteria-tetanus-pertussis (DTP) vaccine provided with or after measles
      vaccine (MV) is associated with increased mortality in areas with herd immunity to pertussis.

      We will examine in a randomised study of 6000 children the effect of not administering DTP
      simultaneously with or after MV on overall child mortality, hospitalization rates, and the
      immunological responses after vaccination. We will also examine potential sex-differential
      effects in the outcomes and interactions with other vaccines, other health interventions and
      season.
    

Detailed description: 
      Background: Infectious diseases are the main cause of high child mortality in Africa. In
      several non-randomised studies, routine childhood vaccinations have been observed to have
      non-targeted effects. Live vaccines like measles vaccine (MV) seem to protect against overall
      mortality, whereas killed vaccines, like DTP, may have no beneficial effects, especially for
      girls. DTP provided with or after MV may be associated with increased mortality. The
      mechanisms behind these effects are unknown.

      Hypothesis: Not providing DTP together with or after MV is associated with a 35 % reduction
      in overall mortality and 23% reduction in hospitalizations.

      Objectives: To examine in a randomised study of 6000 children the effect of not administering
      DTP simultaneously with or after MV on

        1. Overall child mortality

        2. Hospitalization rates and major causes of hospitalization

        3. The immunological profile after vaccination

        4. Sex-differences in the above mentioned outcomes

      Methods:

      Surveillance system: BHP's demographic surveillance system in Bissau covers 6 districts with
      a population of 90,000; 3,500 children are born each year.

      Hospitalizations: There is only one pediatric ward in Bissau and all hospitalizations are
      identified in the BHP register.

      Vaccinations: Vaccinations are provided and registered at the 3 health centres in the study
      area.

      Intervention: In this study 6000 children are randomised as they come to receive DTP3 or DTP
      booster with or after measles vaccination (MV) at the local health centres. Children will be
      randomised to DTP3+OPV3 and MV versus OPV3 and MV or DTP4+OPV4 versus OPV4 (booster doses).

      Follow-up: The children will be followed until 4 years of age or end of study.

        1. Adverse effects: In the first month after vaccination, 1000 children will be visited
           daily for three days and then weekly to register morbidity and consultations.

        2. Hospitalizations: The children will be followed at the pediatric ward.

        3. Mortality: Children will be followed by the routine surveillance system. Furthermore,
           all children will be visited yearly and finally when they reach four years of age. When
           a death is detected, a physician will conduct a verbal autopsy.

      Sample size: With a total of 7500 person-years of follow-up, we will be able to document a
      35% reduction in mortality and a 23% reduction in hospitalizations. A subgroup of children
      will be examined for possible differences in immunological profile after vaccination.

      Ethical considerations: Herd immunity to pertussis should not be affected as, due to the
      intervention, more children is vaccinated.
    

Intervention name(s): DTP3/4+OPV+MV versus OPV+MV or DTP4+OPV4 versus OPV4
Intervention type(s): Biological
Intervention description(s): Trial of not providing 3. and/or 4. DTP together with or after MV at 9 to 18 month of age.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Keywords: Vaccination; DTP; Child mortality; Sex; Non-specific effects