Immunology of Non-specific Effects of Vaccine
Condition: Measles; Diphtheria; Tetanus; Pertussis
MeSH terms: Whooping Cough; Tetanus; Diphtheria; Measles
Study type: Interventional
Phase: Phase 4

Summary: 
      OBJECTIVES

        -  General: To investigate the immunological background for the non-specific effects of
           diphtheria-tetanus-pertussis (DTP) and measles vaccines on child mortality

        -  Specific: Examine the cytokine responses and possible association with morbidity in a
           study of DTP vaccinated children who will be randomised to receive a measles vaccine or
           no vaccine at 4½ months of age. (All children will receive a measles vaccine at 9 months
           of age)
    

Detailed description: 
      Non-specific effects of vaccines The idea of vaccines having non-specific effects was first
      proposed in 1991 from a study in Senegal, West Africa. It was discovered that children
      receiving high-titre measles vaccine (HT) at 6 months of age had higher mortality than
      children who received the standard titre measles vaccine (STD) at 9 months of age. The
      difference was found only for girls. A study from Haiti confirmed the effect. Since children
      vaccinated with HT had lower mortality than their equivalents who had not received any
      measles vaccine, the difference in mortality between recipients of HT vaccine and STD vaccine
      was explained by a non-specific beneficial effect of the STD measles vaccine rather than a
      harmful effect of the HT vaccine. The non-specific beneficial effect of STD measles vaccine
      on child mortality has been reconfirmed in many data-sets.

      Also the BCG vaccine is associated with striking effects on child mortality reducing
      mortality by about 50%. Further, among BCG vaccinated children, having a BCG scar or a
      positive tuberculin reaction was associated with about 55% lower mortality in the following
      12 months than among children who had a negative tuberculin reaction or who did not have a
      BCG scar.

      The effect of OPV is difficult to separate from the effects of BCG and DTP vaccines since OPV
      is normally given together with these vaccines. There have, though, been some periods without
      DTP in Bissau due to global shortage of vaccines, and we have compared the case fatality at
      the hospital for children who received only OPV and children who received both the prescribed
      OPV and DTP. Children having received OPV had 3-fold lower mortality than children having
      received both vaccines. Data from an OPV vaccination campaign that took place in
      Guinea-Bissau also suggested a non-specific beneficial effect for the recipients. Further,
      studies from Chile and the Soviet Union have suggested that OPV had a beneficial effect on
      mortality and morbidity.

      In contrast, DTP, HBV and inactivated polio vaccine (IPV) seem to exert a non-specific
      detrimental effect on child mortality, although the findings on DTP were considered
      controversial by a recent review. Current studies indicate that the negative effect of DTP
      may be neutralized by a subsequent measles vaccination. It is striking that all the vaccines
      with a non-specific beneficial effect are live, whereas the vaccines with an apparently
      harmful effect are killed. Results from animal studies have shown that attenuated live
      vaccines tend to induce a Th1 response and offer better protection against severe disease
      than the corresponding inactivated vaccines, which tend to induce a Th2 response. So far,
      very few studies have examined whether these effects differ between male and female animals.
      One study reported that BCG-vaccinated female mice were better protected against malaria
      parasites than male mice (31). There is therefore an urgent need to conduct studies that can
      help uncover the immunology behind the non-specific effects.

      Sex-specific effects All epidemiological studies carried out so far confirms the observation
      that non-specific effects are sex-specific. Live vaccines (measles, BCG, OPV) have a
      beneficial effect that is particularly good for girls whereas inactivated vaccines (DTP, HBV,
      IPV) have a negative effect for girls. To date, there are no immunological studies which have
      examined whether routine vaccines affect the immune system differently for boys and girls.

      We thus propose to study, in a randomised controlled trial of measles vaccination taking
      place in Guinea-Bissau, the immunology of non-specific effects of vaccination, and their
      interaction with sex. Specifically, among children who have received the 3 recommended doses
      of DTP, we will be able to compare the cytokine and antibody profiles of children who receive
      an early dose of measles vaccine at 4½ months of age with children who receive no additional
      vaccine at this age.
    

Intervention name(s): Measles vaccine
Intervention type(s): Biological
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Non-specific effects of vaccines; Immunology; Cytokines; Infant mortality; Child mortality; Mortality; Morbidity; Diphtheria-tetanus-pertussis vaccine; Measles vaccine; Measles; Immunisation; Low income country; Guinea-Bissau; Bandim Health Project; Immunology of measles and DTP vaccination