BMJ 2000;321:1435 [Full] ( 9 December )
Papers
Routine vaccinations and child survival: follow up study in
Guinea-Bissau, West Africa
Commentary: an unexpected finding that needs
confirmation or rejection
Routine vaccinations and child survival: follow up study in
Guinea-Bissau, West Africa
Ines Kristensen, physician a, Peter Aaby, anthropologist a, Henrik Jensen, statistician b. a Bandim Health Project, Apartado 861, Bissau,
Guinea-Bissau, b Danish Epidemiology Science
Centre, Statens Serum Institut, Copenhagen, Denmark
Correspondence to: P Aaby,
Department of Epidemiology Research, Statens Serum Institut,
Artillerivej 5, 2300 Copenhagen S, Denmark psb{at}sol.gtelecom.gw
 |
Abstract |
Objective:
To examine the association between routine childhood vaccinations and survival among infants in Guinea-Bissau.
Design:
Follow up study.
Participants:
15 351 women and their children born
during 1990 and 1996.
Setting:
Rural Guinea-Bissau.
Main outcome measures:
Infant mortality over six
months (between age 0-6 months and 7-13 months for BCG, diphtheria,
tetanus, and pertussis, and polio vaccines and between 7-13 months and
14-20 months for measles vaccine).
Results:
Mortality was lower in the group vaccinated with any vaccine compared with those not vaccinated, the mortality ratio being 0.74 (95% confidence interval 0.53 to 1.03). After cluster, age, and other vaccines were adjusted for, BCG was associated with significantly lower mortality (0.55 (0.36 to 0.85)). However, recipients of one dose of diphtheria, tetanus, and pertussis or polio
vaccines had higher mortality than children who had received none of
these vaccines (1.84 (1.10 to 3.10) for diphtheria, tetanus, and
pertussis). Recipients of measles vaccine had a mortality ratio of 0.48 (0.27 to 0.87). When deaths from measles were excluded from the
analysis the mortality ratio was 0.51 (0.28 to 0.95). Estimates were
unchanged by controls for background factors.
Conclusions:
These trends are unlikely to be explained exclusively by selection biases since different vaccines were associated with opposite tendencies. Measles and BCG vaccines may have
beneficial effects in addition to protection against measles and tuberculosis.
| |
Introduction |
Measles vaccine is strongly associated with better childhood
survival in developing countries.
1 2
Since this effect
cannot be explained by the specific prevention of
measles,
1 3 4
standard measles vaccine may be associated
with a non-specific beneficial activation of the immune
system.1 This effect would be observed only in areas with
high mortality.5 Similar studies of BCG, polio, and
diphtheria, tetanus, and pertussis vaccines have not been carried out
in countries with a high mortality.
Worldwide, BCG is the most widely used vaccine and has been recommended
for tuberculosis control in developing countries for more than 40 years. The protection provided by BCG is controversial as it has
variable efficacy in different settings.
6 7
Routine vaccinations with diphtheria, tetanus, and pertussis vaccine and polio
vaccine provide good protection against the specific diseases. The
recommended schedule is based on studies of seroconversion and
protection and on assumed feasibility of the schedule.8 The effect of these vaccines has been assumed to be proportionate to
the impact of the specific infections.
Guinea-Bissau in West Africa is one of the world's poorest countries.
It has the sixth highest childhood mortality according to Unicef
estimates.9 Since the early 1990s we have followed a
representative cohort of 10 000 mothers and their children from the
rural areas of Guinea-Bissau. Because the survival of recipients of
routine vaccines has not been investigated in areas with high mortality, we examined the association between vaccination and survival
in rural Guinea-Bissau.
| |
Participants and methods |
Cohort study
A longitudinal study of women of fertile age and their
prospectively registered offspring was initiated in 1990 in the five
most populous regions of Guinea-Bissau. The study was set up to assess
mortality, including perinatal, childhood, and maternal
mortality,10 and to monitor the use of health services. In
each region, 20 clusters of 100 women were selected by the method
recommended by the Expanded Programme on Immunisation for surveys of
immunisation coverage. The children were followed to death, migration,
or the age of 5 years; there was no loss to follow up because it was
always possible to get information on all children from relatives
living in the same compound. Data were collected by a mobile team of
five to six assistants from the Bandim Health Project.
Vaccination status
The vaccination schedule recommended in Guinea-Bissau is BCG and
polio at birth; diphtheria, tetanus, and pertussis and polio at 6, 10, and 14 weeks; and measles at 9 months of age. At each visit,
vaccination status was determined by inspection of the immunisation
card. Children who had no date on their card or who were declared to
have received no vaccination were considered unvaccinated. We excluded
children whose cards could not be inspected because the mother was
absent or the card could not be found. Since we could not advise
communities about the team's visit, many mothers were away on the day
of the visit. Most mothers in rural Guinea-Bissau keep their
children's vaccination cards with their personal belongings locked in
a trunk. Hence, if the mother was not present, the vaccination card
could not be seen.
Analysis and statistical methods
We estimated the effect of vaccinations by analysing mortality
according to the vaccination status assessed at the initial visit.
Information on deaths was obtained at the subsequent visit, and
therefore children had to be visited twice to be included in the study.
Intervals between visits were mostly 5 to 7 months but could be longer
for logistic reasons, particularly because of inaccessibility during
the rainy season. To minimise variability in length of follow up,
mortality was assessed between the initial visit and the date of the
following visit or six months later, if the following visit occurred
more than six months later. As children were 0-6 months old when first
seen, the impact of BCG, polio, and diphtheria, tetanus, and pertussis
vaccines was assessed between the initial visit and the following visit
or six months later. Survival over a longer follow up period would be
confounded increasingly by the effect of measles vaccine. We calculated
estimates separately for recipients of polio and diphtheria, tetanus,
and pertussis vaccines, but these were virtually identical as the two
vaccines are always administered together. The effect of measles
vaccine was examined between the second visit at 7-13 months of age and
the subsequent visit or six months later.
We examined differences in the prevalence ratio for background factors
for vaccinated and unvaccinated children using a generalised linear
model with binomial variability and a logarithmic link function
adjusting for age.
11 12
We also corrected for cluster using generalised estimation equations with an exchangeable correlation structure corresponding to a random cluster effect.13
To estimate the mortality ratio for vaccinated and unvaccinated
children, we used a Cox proportional hazards model,14
taking length of follow up into consideration and adjusting by
stratification for age, period, season, and cluster. By stratifying for
cluster we also controlled for differences between the five regions; in fact, we compared survival for vaccinated and unvaccinated children in
the same village. Vaccination coverage has changed over time as have
death rates, and control for period was therefore important. Since most
vaccines are given in campaigns during the dry season from November to
June, and mortality is higher in the rainy season, it was also
essential to control for season. Neither season nor period affected the
estimates of mortality associated with vaccination, and the results are
therefore not reported here (data available on request). Other
background factors were controlled for in the same Cox model. Mortality
differences between vaccinated and unvaccinated children were also
estimated with other statistical models, but the results were
essentially the same (data available on request).
| |
Results |
Study population and vaccination coverage
Between February 1990 and April 1996, we registered 15 351 women
of fertile age and 11 460 pregnancies; 392 women moved before giving
birth. The 11 068 pregnancies resulted in 333 abortions, and 437 stillbirths. This left 10 298 children, of whom 686 died, 90 moved
before the first visit, and 770 were too young to have received two
visits and could therefore not be included in the survival analysis.
The remaining 8752 children were alive at the first visit and their
survival ascertained at the second visit; 8104 were under 7 months old
when first seen. Of the 8752 children, 429 died and 214 moved between
the first and second visit, and 752 had no third visit before the end
of the study, leaving 7357 children to be followed between the second and third visit. Of the 7357 children, 323 died and 183 moved before
the third visit.
At the first visit, 5754 (66%) had their vaccination card inspected;
2981 (34%) were absent and 17 (0.2%) had lost their card. Eight per
cent of the children received BCG within the first two days of life and
50% (3388/6771) within the first month, the median age of vaccination
being 31 days. The median age for first diphtheria, tetanus, and
pertussis dose was 87 days.
Of the 8104 children aged 0-6 months, 5274 had a vaccination card
examined or had had no card; 63% (3301/5274) were vaccinated with BCG.
Of the 2830 children whose vaccination card was not seen at the first
visit, 1094 had their card examined at the following visit and 53%
(576/1094) had had BCG vaccination before the first visit. Hence,
children whose card was not seen at the initial visit constitute a
travelling group less likely to turn up at the following visit and with
a lower BCG coverage (relative risk=0.82, 95% confidence interval 0.77 to 0.88). For the assessment of measles vaccine, 7357 children were
alive at the second visit and examined at the third visit; 4230 (58%)
had their vaccination card inspected, 3091 (42%) were absent, and 36 (0.5%) had lost the card or had missing information. The median age
for measles vaccination was 10.6 months. Table 1 shows vaccine coverage
at ages 0 and 18 months.
We examined differences in background factors for vaccinated and
unvaccinated children controlling for age and cluster (table 2).
Vaccinated children had more contact with the health system, their
mothers being more likely to have received tetanus vaccination during
pregnancy and to have given birth outside the home. Vaccinated children
had larger arm circumference and their mothers tended to be younger and
have fewer children, to have a latrine in their compound, and not to
belong to the Balanta or Pepel ethnic groups.
View this table:
[in this window]
[in a new window]
|
Table 2.
Prevalence ratio of background factors for
vaccinated and unvaccinated children according to type of vaccine,
Guinea-Bissau, 1990-6
|
|
BCG vaccine
Mortality for the 5274 children aged 0-6 months was lower in the
group vaccinated with any vaccine compared with those not vaccinated,
the mortality ratio being 0.74 (95% confidence interval 0.53 to 1.03).
For children vaccinated with BCG the mortality ratio was 0.72 (0.54 to
0.96) (table 3, fig 1). The ratio became 0.55 (0.36 to 0.85) after age,
diphtheria, tetanus, and pertussis vaccine, and cluster were adjusted
for; estimates varied between 0.50 and 0.58 and were significant when
background factors were controlled for. If we excluded children who
were considered unvaccinated because they had no vaccination card, the
mortality ratio for BCG vaccine among children who were seen was 0.33 (0.17 to 0.65).
View this table:
[in this window]
[in a new window]
|
Table 3.
Mortality during six months of follow up
according to BCG vaccination status and age at intial visit,
Guinea-Bissau, 1990-6
|
|
View larger version (14K):
[in this window]
[in a new window]
|
Fig 1.
Kaplan-Meier survival curves for children who
did and did not receive BCG vaccine. Six months' follow up of 5274 children aged 0-6 months at initial visit, Guinea-Bissau,
1990-6
|
|
The effect of BCG was stronger when the analysis was restricted to
infants aged 0 to 2 months, who would not receive measles vaccine
during the next six months (mortality ratio 0.43 (0.25 to 0.75)). Since
children weighing less than 2500 g are not supposed to receive BCG,
unvaccinated children could represent a negatively selected group.
After 31 days of age all children would presumably weigh more than
2500 g; we therefore analysed data on children aged 1 to 2 months who
were either unvaccinated or vaccinated with BCG after 31 days of life.
The protective effect of BCG was high in this subgroup (0.19 (0.04 to
0.95)).
Diphtheria, tetanus, and pertussis and polio vaccines
Since diphtheria, tetanus, and pertussis and polio vaccines are
administered from 6 weeks of age, the analyses were limited to children
aged 1.5-6 months at the initial visit. Of the 5274 children examined
at 0-6 months of age, 3972 were aged 1.5-6 months; 1822 had no dose of
diphtheria, tetanus, and pertussis vaccine (72 died before the second
visit), 1295 had received one dose (62 died), and 855 had had two or
more doses (32 died). After age, BCG vaccination, and cluster were
adjusted for in a Cox analysis estimating the effect of one and two to three doses separately, one dose of diphtheria, tetanus, and pertussis vaccine was associated with a mortality ratio of 1.84 (1.10 to 3.10)
and two to three doses with a ratio of 1.38 (0.73 to 2.61) compared
with children who had received no dose of these vaccines (table 4).
Estimates were similar for polio vaccine, one dose being associated
with a mortality ratio of 1.81 (1.07 to 3.05) and two to three doses
with a ratio of 1.39 (0.73 to 2.64). Mortality was also increased in
the analysis combining one to three doses of diphtheria, tetanus, and
pertussis (1.72 (1.03 to 2.87)) and diphtheria, tetanus, and pertussis
or polio vaccine (1.67 (1.00 to 2.77) fig 2). Estimates for one dose of
diphtheria, tetanus, and pertussis vaccine varied between 1.72 and 1.98 when background factors were controlled for. However, adjustment for
arm circumference increased the effect of one dose of diphtheria,
tetanus, and pertussis to 2.50 (1.31 to 4.78). If we excluded children
considered unvaccinated because they had no card, the mortality ratio
for one to three doses of diphtheria, tetanus, and pertussis vaccine
among children whose card was seen was 1.78 (1.05 to
3.02)
View this table:
[in this window]
[in a new window]
|
Table 4.
Mortality during six months of follow up among
children who did and did not receive one dose of diphtheria, tetanus,
and pertussis vaccine* according to BCG vaccination status and age at
inital visit, Guinea-Bissau, 1990-6
|
|
View larger version (18K):
[in this window]
[in a new window]
|
Fig 2.
Kaplan-Meier survival curves for recipients of
BCG , recipients of BCG and at least one dose of diphtheria, tetanus,
and pertussis (DTP) or polio vaccine, and non-recipients of all
vaccines. Six months' follow up of 3972 children aged 1.5-6 months at
initial visit, Guinea-Bissau, 1990-6
|
|
Measles vaccine
Children aged 7 to 13 months who had received measles vaccine at
the second visit had a mortality ratio of 0.51 (0.30 to 0.85) compared
with unvaccinated children (table 5 ; fig 3). The ratio was 0.48 (0.27 to 0.87) after age, BCG vaccination, and cluster were adjusted
for and varied from 0.45 to 0.56 when background factors were
controlled for, all estimates except one being significant. The
estimate was unaffected by controls for other vaccinations. If we
excluded children considered unvaccinated because they had no card, the
mortality ratio for measles vaccine among children whose card was seen
was 0.48 (0.27 to 0.87). The reduction in mortality was unrelated to
measles deaths; 9 of 94 deaths in the unvaccinated and 1 of 19 deaths
in the vaccinated groups were reported to be due to measles (table 5).
When deaths from acute measles were excluded, the mortality ratio was
0.51 (0.28 to 0.95) for children vaccinated against measles compared with initially unvaccinated
children.
View this table:
[in this window]
[in a new window]
|
Table 5.
Mortality during six months of follow up
according to measles vaccination status and age at start of six months,
Guinea-Bissau, 1990-6
|
|
View larger version (13K):
[in this window]
[in a new window]
|
Fig 3.
Kaplan-Meier survival curves for recipients and
non-recipients of measles vaccine. Six months' follow up of 3414 children initially aged 7-13 months, Guinea-Bissau, 1990-6
|
|
Early and later vaccination
Many children, although classified as unvaccinated initially,
received vaccination before the next visit. As information was
unavailable for children who moved, died, or were travelling, these
additional vaccinations could not be included in the survival analysis.
To estimate the effect of BCG and diphtheria, tetanus, and pertussis or
polio vaccination of initially unvaccinated children, we assessed
mortality between the second and third visits for children vaccinated
before or after the first visit; for measles vaccine we examined
mortality between the third or fourth visits. Of 1168 children who had
not received BCG vaccine at the first visit, 765 (65.5%) had received
BCG at the second visit. There was no difference in mortality between
those who received vaccine early or late (mortality ratio 1.36 (0.73 to
2.53) after age, diphtheria, tetanus, and pertussis vaccine, and
cluster were adjusted for). Of 1082 children who had not received
diphtheria, tetanus, and pertussis vaccine at the first visit, 772 (71.3% had received at least one dose at the second visit, with no
difference between those who received vaccine early or late (1.10 (0.59 to 2.03)). Of 1371 children who had not received measles vaccine at the
second visit, 864 (63.0%) had received measles vaccine at the
third visit, with no difference in mortality between those who received
the vaccine early or late (1.07 (0.40 to 2.87)).
Infants whose mothers were not at home to show a vaccination card could
constitute a special group in which vaccination had a different effect.
We therefore examined whether the effect of measles vaccination on
children absent at the first visit but seen at the second visit was
different from that in other children. There was no such difference;
the mortality ratio for measles vaccination compared with no measles
vaccination was 0.39 (0.13 to 1.19) for children whose card had not
been seen in the first round and 0.52 (0.27 to 0.99) for children whose
vaccination card had been seen during the first round.
| |
Discussion |
Research on vaccines in developing countries recommended by the
World Health Organization has emphasised serological responses and
protection against specific diseases.1 The aim of the
research has been to optimise vaccine schedules for control,
elimination, or eradication of disease. In modelling exercises,
vaccination against diphtheria, pertussis, tetanus, and polio has been
assumed to save 1.5-2.0% of the children in areas with high infant
mortality.15 However, these assumptions are not supported
by data, and few studies of the effect of routine vaccinations other
than measles on mortality have been carried out in developing
countries.16 Case-control studies in Benin and Brazil
found that BCG vaccination is associated with better
survival.
17 18
We reported from Senegal that
children receiving diphtheria, tetanus, and pertussis vaccination had
slightly higher mortality (mortality ratio=1.59 (0.76 to
3.33)),1 and a case-control study from Benin of 74 children who died had a similar finding (odds ratio=2.20
(0.93-5.22)).17
Methodological issues
In Guinea-Bissau, we found that BCG and measles vaccines were
associated with better survival and diphtheria, tetanus, and pertussis
and polio vaccines with higher mortality compared with no vaccination.
The estimates are unlikely to be due to registration problems. The
initial recruitment for the study was based on a random selection of
clusters. The survival analysis had no loss to follow up, and the
statistical model compared only vaccinated and unvaccinated children
from the same community. We got information on vaccination status for
around two thirds of the children, a high proportion given that the
communities were not informed beforehand about the day of the visit.
Furthermore, there was no indication that those not presenting a
vaccination card reacted differently to the vaccines. Vaccines are
appreciated by mothers in rural Guinea-Bissau, as shown by the high
coverage for BCG and diphtheria, tetanus, and pertussis and polio
(table 1), and there would seem no reason to fake vaccination dates on
cards. However, some vaccinated children may have been registered as
unvaccinated because a nurse forgot to note the date on the child's
card or a guardian reported the child not having a card. Such
misclassification would lessen rather than exaggerate the mortality
differences presented here.
For methodological reasons, our estimates may be conservative. For all
vaccines, children vaccinated before the initial visit and those
vaccinated later had the same mortality in the following period.
Children who received vaccine after the first visit may have had their
mortality changed to that of children who had been vaccinated at the
first visit. This would reduce the mortality ratio for recipients
versus non-recipients of vaccine.
The effects we observed could be due to behavioural differences between
mothers of vaccinated and unvaccinated children. Mothers of vaccinated
children apparently had more frequent contact with the health care
system (table 22). Having "concerned mothers" could
possibly explain a beneficial effect associated with BCG and measles
vaccines; however, the negative association with diphtheria, tetanus,
and pertussis and polio vaccines is difficult to explain. Alternatively, sick children could be brought more often to health centres and therefore receive more vaccines. This seems unlikely as
vaccine recipients had larger arm circumferences than unvaccinated children (table 2) and it would not explain the better survival of
children who received BCG and measles vaccines.
Do BCG and measles vaccines have a non-specific beneficial
effect?
The reduction in mortality after measles and BCG vaccination is
larger than the proportion of deaths attributed to these diseases among
infants and young children. As in previous studies,1
exclusion of measles deaths did not change the mortality ratio between
vaccinated and unvaccinated children. A similar analysis could not be
made for BCG since infant tuberculosis is poorly defined. Tuberculosis
is estimated to have a much smaller effect on childhood mortality than
measles.19 However, we found that the effect of BCG
vaccine was as large as that of measles vaccine. It therefore seems
implausible that the positive effect is merely due to BCG protecting
against primary tuberculosis. The better survival of BCG recipients is
unlikely to be related to non-vaccination of low birthweight infants
because when we restricted the analysis to children vaccinated after 1 month of age the protective effect of BCG was strengthened. The effect of BCG was not due to early recipients constituting a group with better
survival. Future studies should assess the extent to which the impact
of BCG in childhood can be explained by prevention of tuberculosis.
BCG vaccine has been used to stimulate the immune system in certain
chronic diseases, including cancer.
20 21 22 23
In Guinea-Bissau and the Gambia, early BCG vaccination protected against
atopy,24 and BCG vaccination at birth was associated with
the stimulation of a Th1 type immune response.25 In
Bissau, children with a BCG scar or a positive tuberculin test have
lower mortality than vaccinated children without a scar or tuberculin reaction (unpublished data). The better survival associated with BCG
vaccine could therefore reflect a non-specific protection against other
infections as suggested for measles vaccine.1 Children
vaccinated against diphtheria, tetanus, pertussis, and polio were more
atopic than non-vaccinated children in Bissau.24 The fact
that the adjuvant of diphtheria, tetanus, and pertussis, aluminium
hydroxide, is a strong promoter of a Th2 type immune response in mice
may be important.26
Implications of results
Our results will have to be interpreted with caution. As
randomised trials could not have been organised, other forms of control
of internal consistency and of possible differences between vaccinated
and unvaccinated children have been necessary. Although the vaccinated
and unvaccinated children were not directly comparable, controlling for
differences in cultural and social background factors did not affect
the mortality estimates for the different vaccines. Since virtually all
children do eventually get BCG, polio, and diphtheria, tetanus, and
pertussis vaccines in Guinea-Bissau, we essentially measured the effect
of vaccination in the short period before some children had been
vaccinated. Since subsequent mortality did not differ between children
vaccinated early and late, the results cannot be ascribed to children
who are vaccinated having a different mortality. Our results were also
consistent with the few studies reported previously from other
areas.
1 17 18
Unless selection bias is switching back and forth at different ages, it seems difficult to explain both good
survival for BCG and measles vaccine recipients and poor survival for
recipients of diphtheria, tetanus, and pertussis and polio vaccines.
Some of these vaccines are therefore likely to have major non-specific
effects on child survival.1
We need to determine the biological basis and magnitude of the
non-targeted effects of different vaccines. Such effects will be seen
only in developing countries with high mortality, where vaccine induced
forms of immunostimulation could affect the response to other
infections. 25 If BCG vaccine has beneficial effects, these should be considered when testing new, more specific vaccines against tuberculosis in the future. The use of a new vaccine could be
associated with higher mortality, as was the case when the high titre
measles vaccine was introduced.27 The combined effect of
BCG and polio and diphtheria, pertussis, and tetanus vaccines was
protective against childhood mortality (mortality ratio 0.74, 95%
confidence interval 0.53 to 1.03). Should diphtheria, pertussis, and
tetanus or polio vaccines be found out to have negative effects on
mortality despite their protection against specific diseases, new
vaccine formulations might improve the effect of the vaccination programme.
Our observations emphasise the importance of immunisations in
developing countries; vaccinated children had much lower mortality. However, it may be possible to obtain even better results. The current
vaccination schedule, emphasising three early doses of diphtheria,
tetanus, and pertussis and polio vaccine, is associated with low
coverage for measles vaccine.1 A stronger emphasis on BCG
and measles vaccines would contribute to lower mortality. Hence,
changes in the vaccination schedules28 or type of vaccines used in developing countries could improve coverage and child survival.
|
What is already known on this topic
Measles vaccine may be associated with a non-specific survival benefit
in countries with a high mortality
No attempt has been made to assess the effect of other routine
immunisations on mortality in developing countries
What this study adds
BCG and measles vaccines were associated with reductions in mortality
in rural Guinea-Bissau
The effect for measles vaccine could not be explained by the prevention
of measles infection
Diphtheria, tetanus, and pertussis and polio vaccines were associated
with higher infant mortality
Non-specific effects of routine immunisations should be considered when
planning immunisation programmes in developing
countries
|
| |
Acknowledgments |
Contributors: IK supervised the last year of data
collection and wrote the first draft of the paper. HJ supervised data
control and carried out the statistical analyses. PA initiated the
study, supervised data collection, carried out the first analyses, and
wrote the final version of the paper. HJ and PA will act as guarantors.
| |
Footnotes |
Funding: Ministry of Public Health, Guinea-Bissau; Unicef,
Guinea-Bissau; Danish Council for Development Research; Danish Medical
Research Council; and European Union's science and technology for
development programme (TS3*CT91*0002 and ERBIC 18 CT95*0011).
Competing interests: None declared.
| |
References |
| 1.
|
Aaby P, Samb B, Simondon F, Coll Seck AM, Knudsen K, Whittle H.
Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries.
BMJ
1995;
311:
481-485[Abstract/Free Full Text].
|
| 2.
|
Aaby P, Andersen M, Sodemann, Jakobsen M, Gomes J, Fernandes M.
Reduced childhood mortality following standard measles vaccination at 4-8 months compared with 9-11 months of age.
BMJ
1993;
307:
1308-1311.
|
| 3.
|
Koenig MA, Khan MA, Wojtyniak B, Clemens JD, Chakraborty J, Fauveau V, et al.
The impact of measles vaccination upon childhood mortality in Matlab, Bangladesh.
Bull WHO
1990;
68:
441-447[Medline].
|
| 4.
|
Aaby P, Pedersen IR, 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:
197-200[Medline].
|
| 5.
|
Aaby P, Samb B, Simondon F, Knudsen K, Coll Seck AM, Bennett J, et al.
A comparison of vaccine efficacy and mortality during routine use of high-titre Edmonston-Zagreb and Schwarz standard measles vaccines in rural Senegal.
Trans R Soc Trop Med Hyg
1996;
90:
326-330[CrossRef][Medline].
|
| 6.
|
Rodrigues LC, Diwan VK, Wheeler JG.
Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis.
Int J Epidemiol
1993;
22:
1154-1158[Abstract/Free Full Text].
|
| 7.
|
Fine PEM.
Variation in protection by BCG: implications of and for heterologous immunity.
Lancet
1995;
346:
1339-1345[CrossRef][Medline].
|
| 8.
|
Ramsay MEB, Rao M, Begg NT, Redhead K, Atwell AM.
Antibody response to accelerated immunisation with diphtheria, tetanus, and pertussis vaccine.
Lancet
1993;
342:
203-205[CrossRef][Medline].
|
| 9.
|
United Nations Children's Fund.
The state of the world's children 1998.
Oxford: Oxford University Press, 1998.
|
| 10.
|
Høj L, Stensballe J, Aaby P.
Maternal mortality in Guinea-Bissau: the use of verbal autopsy in a multi-ethnic population.
Int J Epidemiol
1999;
28:
70-76[Abstract/Free Full Text].
|
| 11.
|
McCullagh P, Nelder JA.
Generalized linear models.
2nd ed.
London: Chapman and Hall, 1989.
|
| 12.
|
Zochetti C, Consonni D, Bertazzi PA.
Estimation of prevalence rate ratios from cross-sectional data.
Int J Epidemiol
1995;
24:
1064-1065[Free Full Text].
|
| 13.
|
Diggle PJ, Liang K-Y, Zeger SL.
Analysis of longitudinal data.
New York: Oxford University Press, 1994.
|
| 14.
|
Cox DR, Oakes D.
Analysis of survival data.
London: Chapman and Hall, 1984.
|
| 15.
|
Jamison DT, Torres AM, Chen LC, Melnick JL.
Poliomyelitis.
In:
Jamison DT, Mosley WH, Measham AR, Bodadilla JL, eds.
Disease control priorities in developing countries.
New York: Oxford University Press, 1993:117-129.
|
| 16.
|
Ivanoff B, Robertson SE.
Pertussis: a worldwide problem. In: Brown F, Greco D, Mastrantonio P, Salmaso S, Wassilak S, eds. Pertussis vaccine trials.
Dev Biol Stand
1997;
89:
3-13[Medline].
|
| 17.
|
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:
474-479[Abstract/Free Full Text].
|
| 18.
|
Niobey FML, Duchiade MP, Vasconcelos AGG, de Cavalho ML, Leal MC, Valente JG.
Fatores de risco para morte por pneumonia em menores de um ano em uma região metropolitana do sudeste do Brasil. Un estudo tipo caso-controle.
Rev Saúde Públ, São Paolo
1992;
26:
229-238.
|
| 19.
|
World Health Organization, United Nations Children's Fund.
State of the world's vaccines and immunization.
Geneva: WHO, 1996.
|
| 20.
|
Lugosi L.
Theoretical and methodological aspects of BCG vaccine from discovery of Calmette e Guerin to molecular biology. A review.
Tuberc Lung Dis
1992;
73:
252-261[CrossRef][Medline].
|
| 21.
|
Rosenthal SR.
Surgery, recall antigens, immunity, and bacillus Calmette-Guerin vaccination.
Am J Surg
1988;
156:
1-3[CrossRef][Medline].
|
| 22.
|
Herr HW, Schwalb DM, Zhang ZF, Sogani PC, Fair WR, Whitmore WF, et al.
Intravesical bacillus Calmette-Guerin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial.
J Clin Oncol
1995;
13:
1404-1408[Abstract].
|
| 23.
|
Ravaud A, Eghbali H, Trojani M, Hoerni-Simon G, Soubeyran P, Hoerni B.
Adjuvant bacillus Calmette-Guerin therapy in non-Hodgkin's malignant lymphomas: long-term results of a randomized trial in a single institution.
J Clin Oncol
1990;
8:
608-614[Abstract].
|
| 24.
|
Aaby P, Shaheen S, Heyes C, Goudiaby A, Shiell A, Jensen H, et al.
Early BCG vaccination and reduction in atopy in Guinea-Bissau.
Clin Exp Allergy
2000;
30:
644-650[CrossRef][Medline].
|
| 25.
|
Marchant A, Goetghebuer T, Ota M, Wolfe I, Ceesay S, Corrah T, et al.
Newborns develop a T helper 1 type response to BCG vaccination.
J Immunol
1999;
163:
2249-2255[Abstract/Free Full Text].
|
| 26.
|
Lindblad EB, Elhay MJ, Silva R, Appelberg R, Andersen P.
Adjuvant modulation of immune responses to tuberculosis subunit vaccines.
Infect Immun
1997;
65:
623-629[Abstract].
|
| 27.
|
Aaby P, Knudsen K, Whittle H, Thårup J, Poulsen A, Sodemann M, et al.
Long-term survival after Edmonston-Zagreb measles vaccination: increased female mortality.
J Pediatr
1993;
122:
904-908[Medline].
|
| 28.
|
Garly ML, Martins CL, Balé C, da Costa F, Dias F, Whittle H, et al.
Early two-dose measles vaccination schedule in Guinea-Bissau: good protection and coverage in infancy.
Int J Epidemiol
1999;
28:
347-352[Abstract/Free Full Text].
|
(Accepted 4 June 2000)
Commentary: an unexpected finding that needs
confirmation or rejection
Paul Fine, professor.
Department of Infectious and Tropical
Diseases, London School of Hygiene and Tropical Medicine, London
WC1E 7HT
pfine{at}lshtm.ac.uk
The paper from Guinea Bissau in this issue, on routine
vaccinations and child survival, may cause concern. An observational study undertaken under difficult circumstances, it reports three surprising trends: lower than expected mortality associated with BCG
and with measles vaccines and higher than expected relative mortality
associated with diphtheria-tetanus-pertussis(DTP)-polio vaccine, each
of them just over the edge of conventional statistical significance.
One should first question whether the results are valid. This is
ostensibly a cohort study, following-up infants with different initial
vaccination status, but the design and presentation are complicated.
Of paramount importance is the comparability of the groups being
compared. Vaccines are not distributed at random anywhere, and this may
be particularly so in as disadvantaged a population as that in Guinea
Bissau. The assignation of vaccination status in this study is not
entirely clear, as written records were not available for a high
proportion of infants and we are told of infants "who were declared
to have received no vaccination." Table 2 gives a breakdown of
variables associated with vaccination status, and, not surprisingly,
all vaccines appear to be associated with greater than average use of
health services (mothers of vaccinated infants were 1.2 times more
likely to have received tetanus vaccines than were mothers of
non-vaccinated children). Might this explain the higher survival of
recipients of BCG and measles vaccines? The table also shows that
mothers of recipients of DTP-polio vaccine were younger than those of
recipients of BCG or measles vaccines, though we do not know why. But
we do know that high infant mortality is associated with low maternal
age1: is it a coincidence that infants of these young
mothers had a relative increase in mortality? The authors have adjusted
for "background factors," but exactly which factors were included
is not clear, and, given the complexity of these trends, it is unlikely
that the groups were fully comparable as a result.
The numerical results are anomalous. In all the tables we see evidence
of decreasing mortality with increasing age at start of follow up among
the unvaccinated infants, as expected; but in both the BCG and DTP
tables we see increasing mortality with age among infants
who were vaccinated. This is contrary to expectation, and is not
discussed. Such trends may reflect small numbers, but so may the
overall associations of mortality with vaccination status, as the
significance of each depends on a single or very few events. It is
strange that the effect of DTP is associated with one dose but is not
significant for two or three doses
which is not what we expect of a
causal influence. The results thus fall short on three of the classic
attributes of causality: gradient, strength, and coherence.
Beyond the issue of validity, the paper is potentially misleading in
its description of the apparent influence of DTP-polio vaccine. Given
that DTP was tightly linked to prior BCG vaccination (only 19 infants
received DTP without prior BCG), the effect of the DTP-polio vaccines
could only be assessed against a background of BCG vaccination, and the
observed result might better be described in terms of reducing the
survival advantage associated with BCG vaccines than as increasing
mortality (fig 2).
Should we discard the results as unconvincing, or consider further what
they might imply if true? If the latter, then we have hints of
different, non-specific, short term effects on mortality associated
with different vaccines in early life, in a population with high infant
mortality. There are precedents for some such effects, in particular
studies which have suggested non-specific reductions in childhood
mortality associated with measles vaccines.2 The extent
and biological implications of that association are not yet clear. The
issue of non-specific effects of infections and vaccines has become
fashionable recently, in particular with reference to allergic
phenomena, but even in this case the evidence is observational and not
consistent.
3 4
To attribute such effects to shifts
towards Th1 or Th2 type immune responses is also fashionable but
controversial and probably an oversimplification.5 In the
broader context, a full assessment of benefits and risks of vaccines
must take into account the diseases against which the vaccines are
designed to protect and whose frequency may have been decreased by the
vaccines.6
This paper may raise questions about the standards of evidence
appropriate for publication of unexpected versus coherent effects of
interventions. The findings reported here are not convincing in
themselves, though they would be important if true. There are thus many
facets to this problem, and appropriate studies, carefully designed and
analysed, and thoroughly presented, are needed.
| |
References |
| 1.
|
Hobcraft JN, McDonald JW, Rutstein SO.
Demographic determinants of infant and early child mortality: a comparative analysis.
Population Studies
1985;
39:
363-385[CrossRef].
|
| 2.
|
Aaby P, Samb B, Simondon F, Coll Seck AM, Knudsen K, Whittle H.
Non-specific beneficial effects of measles immunisation: analysis of mortality studies from developing countries.
BMJ
1995;
311:
481-485.
|
| 3.
|
Strachan DP.
Lifestyle and atopy.
Lancet
1999;
353:
1457-1458[CrossRef][Medline].
|
| 4.
|
Aaby P, Shaheen SO, Heyes CB, Goudiaby A, Hall AJ, Shiell AW, et al.
Early BCG vaccination and reduction in atopy in Guinea Bissau.
Clin Exper Immunol
2000;
30:
644-650.
|
| 5.
|
Power CA, Wei G, Bretscher PA.
Mycobacterial dose defines the Th1/Th2 nature of the immune respose independently of whether immunization is administered by the intravenous, subcutaneous or intradermal route.
Infect Immun
1998;
66:
5743-5750[Abstract/Free Full Text].
|
| 6.
|
Fine PEM, Clarkson JAC.
Individual versus public priorities in the determination of optimal vaccination policies.
Am J Epidemiol
1986;
124:
112-120.
|
© BMJ 2000
Abstract
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
