Measles immunisation and socioeconomic confounding
Measles immunisation causes a spectacular reduction of 30% to 86% in
child mortality in developing countries (1). The benefit is greatest in
the 6-12 months after immunisation, and in infancy (44% to 100%). Dr
Dalton (2nd July 1999) and Dr Emerton (20th July 1999) wonder whether the
apparent benefit from measles immunisation might be due to better
nutrition and better health care in children who receive measles vaccine
(socioeconomic confounding), rather than an effect of the vaccine. In the
absence of any large randomised controlled trials of measles vaccine in
developing countries, socioeconomic confounding cannot be excluded – but
it is highly unlikely, for several reasons.
First, in the only placebo controlled trial of measles vaccine in a
developing country (2), none of the 23 vaccinated children died compared
to 3 (12%) of the 25 unvaccinated children.
Second, in a natural experiment in Bissau (3), some children were
accidentally injected with an ineffective vaccine (given on five
consecutive vaccination days over a 3 week period). There was no
selection bias in this study because all the children were immunised.
From the time of vaccination to 3 years of age, the mortality rate was
4.5% in 124 children who seroconverted after active vaccine and 15.1% in
53 children given ineffective vaccine.
Third, in two large studies in Zaire (4) and Bangladesh (5),
confounding is unlikely because measles vaccine was made available in half
the study area and not in the other. The two areas had similar mortality
rates before immunisation. Immunisation reduced mortality by 42% in Zaire
and by 46% in Bangladesh.
Fourth, studies that have controlled for socioeconomic factors have
still found that measles immunisation reduced mortality by 36% to 90%(1).
Fifth, measles immunisation is unlikely to be merely a marker for
better health care because the reduction in mortality is greatest in the
12 months after measles immunisation (and the benefit of better health
care should persist), and diphtheria-tetanus-pertussis immunisation is not
associated with reduced mortality (6).
Measles immunisation causes a much greater fall in mortality than the
proportion of deaths attributed to measles, particularly in girls (1). Is
this because measles causes many more deaths than we realise (from delayed
effects of the disease, or from subclinical infection), or does the
vaccine reduce mortality from conditions other than measles?
The large reduction in mortality after immunisation is unlikely to be
due to the prevention of delayed deaths from measles because immunised
children who have not had measles have a much lower mortality than
unimmunised children who have not had measles (1). Subclinical measles
infection is certainly common in both immunised and unimmunised children
in developing countries, however such infections have no effect on
nutritional indices or mortality (7).
In randomised controlled trials in Guinea-Bissau (8) and Senegal (9),
children were given high-titre Edmonston-Zagreb (EZ) vaccine at 4-5 months
of age or standard Schwarz vaccine at 9-10 months. In the two trials,
girls given EZ vaccine had a mortality rate that was 1.95 and 1.76 times
respectively that of girls given Schwarz vaccine. This occurred despite
the fact that there is a good antibody response to high-titre EZ vaccine
at 4-5 months, and there was no increase in measles in the EZ group. Both
vaccines protected against measles, but the Schwarz vaccine also protected
girls against diseases other than measles. These were both randomised
trials, so socioeconomic confounding is very unlikely to be the
explanation for this remarkable finding.
It is crucial that the main message is not lost in the debate about
cause and effect. Measles immunisation clearly causes a spectacular
reduction in mortality in children in developing countries, and this
effect is probably enhanced by a two-dose schedule with immunisation at 6
and 9-12 months. Far greater effort should go into seeing that all
children receive measles vaccine and, if measles is ever eradicated,
controlled trials will be needed to see whether the vaccine should still
be given to children in countries with high child mortality rates.
Intensive Care Unit, Royal Children's Hospital,
Melbourne, Victoria 3052, Australia
Department of Epidemiology Research, Statens Serum Institut,
Artillerivej 5, 2300 Copenhagen S, Denmark
1. Aaby P, Samb B, Simondon F, Seck AMC, Knudsen K, Whittle H. Non-
specific beneficial effect of measles immunisation: analysis of mortality
studies from developing countries. BMJ 1995;311:481-5.
2. Hartfield J, Morley D. Efficacy of measles vaccine. J Hygiene
3. Aaby P, Pedersen IBR, Knudsen K, da Silva MC, Mordhorst CH, Helm-
Petersen NC et al. Child mortality related to seroconversion or lack of
seroconversion after measles vaccination. Pediatr Infect Dis J 1989;8:197
4. Kasongo Project Team. Influence of measles vaccination on survival
pattern of 7-35-month-old children in Kasongo, Zaire. Lancet 1981;1:764-
5. Koenig MA, Khan MA, Wojtyniak B, Clemens JD, Chakraborty J,
Fauveau V et al. Impact of measles vaccination on childhood mortality in
rural Bangladesh. Bull WHO 1990;68:441-7.
6. Velema JP, Alihonou EM, Gandaho T, Hounye FH. Childhood mortality
among users and non-users of primary health care in a rural West African
community. Int J Epidemiol 1991;20:474-9.
7. Bennett J, Whittle H, Samb B, Cisse B, Simondon F, Aaby P.
Seroconversions in unvaccinated infants: further evidence for subclinical
measles from vaccine trials in Niakhar, Senegal. Int J Epidemiol
8. Aaby P, Knudsen K, Whittle H, Lisse IA, Thaarup J, Poulsen A et
al. Long-term survival after Edmonston-Zagreb measles vaccination in
Guinea-Bissau: increased female mortality rate. J Pediatr 1993;122:904-8.
9. Aaby P, Samb B, Simondon F, Knudsen K, Seck AMC, Bennett J et al.
Sex-specific differences in mortality after high-titre measles
immunization in rural Senegal. Bull WHO 1994;72:761-770.
Competing interests: No competing interests