Bacillus Calmette-Guerin (BCG) Vaccine and Morbidity From Malaria
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 3

Summary: 
      BCG vaccine is given at or shortly after birth in many developing countries to prevent
      tuberculosis. In Guinea Bissau, it has been shown that its protective effect against death is
      greater than would be expected from its effect against tuberculosis. This observation
      suggests that BCG may enhance the ability of the immune system of young children to make a
      protective response to other infections, including malaria. There is some evidence to support
      this hypothesis as BCG protects against malaria in experimental animals.

      Because BCG is a recommended vaccine, a randomised controlled trial of BCG at birth would not
      be ethically justifiable. However, it is not known whether re-vaccination with BCG in the
      second year of life might provide some added benefit and a large study to determine this is
      under way in Guinea Bissau. This study examined the effect of re-vaccination with BCG on the
      incidence of clinical malaria. If re-vaccination with BCG at 19 months of age is found to
      protect against malaria this would support the hypothesis that one of the ways that BCG at
      birth provides protection to young children is through an effect on malaria.
    

Detailed description: 
      Background

      Studies undertaken in Guinea Bissau have shown that the protective effect of BCG vaccine
      against death in young children is greater than would be expected from its effect in
      preventing tuberculosis. How this might be achieved is not known but BCG could act by
      enhancing the immune response to common infections including malaria which is an important
      cause of death in young children in Bissau. There is some laboratory evidence to support this
      hypothesis. BCG prevents malaria in rodents, probably by activating their
      reticulo-endothelial system and Freund's adjuvant, an emulsion of tubercle bacilli in oil,
      prevents malaria in primates.

      In most developing countries, BCG is given as soon as possible after birth and is an integral
      part of the immunisation programme so that a controlled trial which withheld neonatal BCG
      vaccination would not be ethical. However, it is uncertain how long the non-specific
      protective effect of BCG persists and whether this could be sustained by a further injection
      of BCG in the second year of life. A major trial to investigate this possibility is under way
      in Guinea Bissau with mortality as its main end-point. The current study has made use of this
      opportunity to investigate whether or not re-vaccination with BCG has a protective effect
      against malaria.

      Objective

      The primary objective of the study was to determine if re-vaccination with BCG reduced
      morbidity from malaria in young children.

      Study area

      The study was carried out within the area covered by the Bandim Health Project in Bissau, the
      capital of Guinea Bissau, West Africa. The study area, within the suburbs of Bissau, has a
      population of approximately 70,000 who are under demographic surveillance. Routine infant
      immunisations are given at 3 health centers in the area; babies who deliver in the national
      hospital are given BCG before they leave. Overall coverage with BCG is high (> 95%).

      Study population

      All infants resident in the study area were eligible for inclusion in the main BCG
      re-vaccination trial. Children were recruited to the malaria sub-study during the period
      January to October 2003 at the age of 19 months when they were due to receive BCG
      re-vaccination or to remain as a control. Separate, written, informed consent was obtained
      for inclusion in the malaria sub-study.

      Study procedure.

      At the age of 19 months, children whose parents gave consent were allocated randomly to
      receive BCG revaccination or to be a control and entered into the malaria study. Because BCG
      leaves a scar, it was not possible to undertake a double blinded study. However, the field
      staff who assessed the patients for clinical attacks of malaria were unaware of the
      hypothesis underlying the trial and blood films were read without knowledge of an
      individual's study group.

      The prevalence of malaria in children in the two groups was determined through a combination
      of active and passive surveillance. Any child in the study who presented to one of the
      dispensaries in the study area or to the national hospital with an illness suggestive of
      malaria was investigated for possible malaria. If a child had a history of fever or a raised
      axillary temperature (> 37.5 degrees Celsius) blood films were obtained and the hemoglobin
      measured. Children found to have malaria were treated with chloroquine which was the first
      line treatment at the time of the study. In addition to passive surveillance, two cross
      sectional surveys of all children in the study were undertaken at the beginning and at the
      end of the malaria transmission season, during which blood films were collected and the
      hemoglobin measured. Quality control for the reading of blood films was provided by staff of
      the MRC Laboratories, The Gambia.

      Some of the study children with clinical malaria were enrolled in a separate case control
      study of risks for malaria.

      Trial end-point

      The primary trial end-point was the incidence of malaria in children in the two study groups.
      Malaria was defined as the presence of (a) fever or a history of fever,(b) no other obvious
      cause for the fever and (c) the presence of asexual stage Plasmodium falciparum asexual
      parasitemia of any density. For a second definition, a parasite density of 5,000 parasites
      per ul or >, the estimated fever threshold for the study area, was required.

      Sample size

      On the basis of previous experience in the study area, it was estimated that the incidence of
      malaria in children in the control group would be about 0.3 attacks during the malaria
      transmission season. On this basis a study with 600 children in each arm would have 80% power
      at the 5% level of significance to detect a reduction in the incidence of malaria of 25% in
      the children who received BCG. A trial of this size would have 80% power to detect a
      reduction in the prevalence of parasitaemia of 22% at the final cross-sectional survey
      assuming a prevalence in the control arm of 35% asexual P. falciparum parasitemia, an
      assumption based on the results of a previous survey.

      Monitoring

      A Data Safety and Monitoring Board (DSMB) provided supervision for the study and approved the
      analytical plan before the trial code was broken. Monitoring visits were made by scientists
      from the UK and from The Gambia.
    

Intervention name(s): BCG
Intervention type(s): Biological
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Single
Primary purpose: Prevention
Keywords: Malaria; BCG vaccine; Guinea Bissau