Early Two-dose Measles Vaccination Trial
Condition: Measles
MeSH terms: Measles
Study type: Interventional
Phase: Phase 4

Summary: 
      The specific aims are to examine in Guinea-Bissau:

        -  whether the standard titre Schwarz (SW) or standard-titre Edmonston-Zagreb (EZ) measles
           vaccine will be the best vaccine strain for use in a routine one-dose measles
           vaccination schedule and a two-dose measles vaccination schedule in terms of antibody
           response, protection against measles and child survival, and

        -  whether the standard-titre Edmonston-Zagreb (EZ) vaccine will be suitable for use in a
           very early two-dose schedule vaccinating at 4½ and 9 months of age
    

Detailed description: 
      BACKGROUND:

      Two dose schedules:

      After the failure of the high-titre measles vaccine, which was to be administered at 6 months
      of age it was suggested to perform trials of early two-dose measles vaccination schedules to
      lower the age of vaccination. The standard titre SW measles vaccine has been shown to be
      associated with a non-specific beneficial effect on child mortality that cannot be ascribed
      to the protection against measles. The two measles vaccines most commonly used in the
      Expanded Programme on Immunization (EPI) are the standard titre SW and the standard titre EZ
      vaccine. Surprisingly, these two vaccines have never been compared in a randomised trial with
      child mortality as end-point, and it is not clear which would be most suitable for use in a
      two-dose vaccination schedule.

      From 1995 to 2002, all children in the BHP study area were included in an early two-dose
      measles vaccination trial from 6 months of age. The children were randomised to either a
      one-dose group receiving an inactivated polio vaccine (IPV) at 6 months of age and a measles
      vaccine at 9 months of age, or a two-dose group receiving two doses of measles vaccine at 6
      and 9 months of age. For the first 6 months of the trial, the standard-titre EZ measles
      vaccine was used, for the rest of the trial the standard-titre SW vaccine was used. Results
      from the trial showed that an early two-dose schedule increased coverage considerably and
      provided better protection against measles among infants than the recommended one-dose at 9
      months of age schedule. The EZ and the SW vaccine were used in two different cohorts - so a
      direct comparison was not possible, but the EZ vaccine seemed to boost a secondary immune
      response better than the SW vaccine. Further, the SW vaccine was less able to induce a
      protective level of antibodies when used from 6 months of age than the EZ vaccine. The
      preliminary data that we have on long-term vaccine efficacy supports that the SW vaccine
      might be less suitable than the EZ vaccine for use in very early measles vaccine schedules
      (unpublished data). On the other hand, trials performed during the 1980's in Mexico and
      Bangladesh have shown that administration of the standard-titre EZ vaccine to infants as
      young as 4-6 months of age gave good seroconversion results.

      The Global Measles Strategic Plan 2001-2005 developed by the WHO and UNICEF states that all
      children should be guaranteed a second opportunity for measles vaccination either through
      campaigns or routine immunisation. The best strategy for protection of infants living in
      overcrowded urban African societies and who run a great risk of contracting measles before
      the recommended age of immunisation, will probably be early vaccination followed by a second
      vaccination later in childhood. If, in a vaccination campaign strategy, administration of the
      first vaccine is postponed this could dramatically increase the measles incidence in children
      below the age of vaccination. To this add that vaccination campaigns have not yet been
      evaluated in Africa in terms of childhood mortality relative to the routine schedule. Some
      children might get two, three or even more measles vaccines in an uncontrolled and not
      necessarily beneficial manner. Thus finding the best schedule and vaccine strain for use in a
      routine two-dose schedule seems a better approach for this region.

      We thus propose to conduct a study comparing the standard-titre SW measles vaccine and the
      standard-titre EZ measles vaccine in a one- or two-dose schedule providing the first dose at
      9 months of age, and then randomising the children at 18 months of age to receive either an
      additional dose of vaccine or nothing. The groups will be compared in terms of
      seroconversion-rate, proportion with an non-protective antibody level, geometric mean titer
      antibody level, vaccine efficacy, and child mortality. Further we plan to test the
      standard-titre EZ vaccine in a very early two-dose schedule providing the first dose at 4½
      months of age and the second dose at 9 months of age (see also non-specific effect of
      vaccination).

      It is likely that measles elimination vaccination campaigns will take place in the study area
      during the trial. The date of vaccination and the type of measles vaccine used in such
      campaigns will be noted, as well as simultaneous vitamin A supplementation; and the
      information will be included in the final data-analyses.

      Non-specific effect of vaccination:

      The measles vaccine has in several community studies from different parts of the world been
      shown to have a non-specific beneficial effect on child mortality. That means that the
      protection against death mediated by the vaccine exceeds the disease specific effect, ie the
      vaccine not only prevents deaths caused by measles, but also other deaths, presumably due to
      a non-specific immune stimulation providing protection from other infections than measles.
      For example, during the war in Guinea-Bissau that broke out on June 7, 1998, the population
      fled and the health care system broke down. There was no routine vaccination for at least a 3
      months period. Hence, when the war started there was a group of infants who had been
      randomised to early SW measles vaccination at 6 months or IPV and who did not receive the
      standard-titre SW measles vaccine at 9 month that they would otherwise have been given. This
      natural experiment represents the first randomised study of the mortality effect of SW
      measles vaccine. The mortality ratios for measles vaccinated children were 0.29 (0.08-1.03,
      p=0.041) and 0.31 (0.10-0.94) over the first 3 and 7 months of the war.

      Contrary to measles vaccination, diphtheria-tetanus-pertussis (DTP) vaccination has been
      associated with a negative effect on child mortality. Current studies indicate that the
      negative effect of DTP may be neutralized by a subsequent measles vaccination. The design of
      the proposed trial will allow us to test whether the negative effect of the DTP vaccine,
      which is administered by the EPI-programme at 6, 10 and 14 weeks of age, can be reverted by
      administration of a measles vaccine 4 weeks after the last DTP vaccination at around 4½
      months of age.

      Non-specific effects of vaccination are sex-specific. Girls benefit most from beneficial
      non-specific effects, and suffer most from apparently harmful non-specific effects of
      vaccination. Non-specific effects of measles vaccination may also show interaction with
      season, the beneficial effect of measles vaccination being largest in the dry season
      (unpublished), suggesting that some unknown immunological factors play a role. Season has a
      large influence on health in West Africa, and both morbidity and mortality, as well as
      immunologic parameters such as delayed-type hypersensitivity, T-cells, thymus size and
      measles antibody levels which are associated with season.

      We intend to investigate the interactions of sex and season with measles vaccination and will
      assure that data on morbidity and immunologic parameters will be collected both in the dry as
      well as in the rainy season.

      Time table:

      The study began in July 2003, and with a sample size of 5.755 and a possible 2.000 children
      included per year, the inclusion period for the trial will be about 3 years.
    

Intervention name(s): Measles vaccine
Intervention type(s): Biological
Intervention description(s): The children will be randomised to the following three arms:
Arm 1 - Very early two-dose: V (EZ) 4½ mo of age + V (EZ) 9 mo of age.
Arm 2 - 9 months one- or two-dose: V (SW) 9 mo of age + V (SW)/or nothing 18 mo of age.
Arm 3 - 9 months one- or two-dose: V (EZ) 9 mo of age + V (EZ)/or nothing 18 mo of age.
V = measles vaccination, EZ = standard titre Edmonston-Zagreb measles vaccine, SW = standard titre Schwarz measles vaccine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Non-specific effects of vaccines; Infant mortality; Child mortality; Mortality; Morbidity; Diphtheria-tetanus-pertussis vaccine; Measles vaccine; Measles; Immunisation; Low income country; Guinea-Bissau; Bandim Health Project; Immunology