Aim: To assess the cell mediated immune response to BCG vaccine in preterm babies. Methods:Sixty two consecutive preterm babies born at &#60; 35 weeks of gestation were randomly allocated into two groups. Babies in group A were vaccinated early at 34-35 weeks and group B were vaccinated late at 38-40 weeks of postconceptional age. The two groups were similar in terms of: gestational age (mean (SD) 33.1 (1. 1) and 33 (1.2) weeks, respectively); birthweight 1583 (204) and 1546 (218) g; neonatal problems; socioeconomic status; and postnatal weight gain. The cell mediated immune response to BCG was assessed using the Mantoux test and the lymphocyte migration inhibition test (LMIT) 6-8 weeks after BCG vaccination. Induration of >5 mm after the Mantoux test was taken as a positive response. Results:  There was no significant difference in the tuberculin conversion rates (80% and 80.7%, respectively), positive LMIT (86.6% and 90.3%, respectively), or BCG scar (90.0% and 87.1%, respectively) among the two groups. Conclusions: Prematurity seems to be an unlikely cause for poor vaccine uptake. Preterm babies can be effectively vaccinated with BCG at 34-35 weeks of postconceptional age, the normal time of discharge in a developing country

Deorari, Ashok Kumar

Kumar, Ashok

Paul, Vinod kumar

Singh, Meharban

Thayyil-Sudhan, Sudhin

English

Publications of the IAS Fellows

Safety and eVectiveness of BCG vaccination in
preterm babies
Sudhin Thayyil-Sudhan, Ashok Kumar, Meharban Singh, Vinod Kumar Paul,
Ashok Kumar Deorari
Abstract
Aim—To assess the cell mediated immune
response to BCG vaccine in preterm
babies.
Methods—Sixty two consecutive preterm
babies born at < 35 weeks of gestation were
randomly allocated into two groups. Babies
in group A were vaccinated early at 34–35
weeks and group B were vaccinated late at
38–40 weeks of postconceptional age. The
two groups were similar in terms of:
gestational age (mean (SD) 33.1 (1.1) and
33 (1.2) weeks, respectively); birthweight
1583 (204) and 1546 (218) g; neonatal prob-
lems; socioeconomic status; and postnatal
weight gain. The cell mediated immune
response to BCG was assessed using the
Mantoux test and the lymphocyte migra-
tion inhibition test (LMIT) 6–8 weeks after
BCG vaccination. Induration of >5 mm
after the Mantoux test was taken as a posi-
tive response.
Results—There was no significant diVer-
ence in the tuberculin conversion rates
(80% and 80.7%, respectively), positive
LMIT (86.6% and 90.3%, respectively), or
BCG scar (90.0% and 87.1%, respectively)
among the two groups.
Conclusions—Prematurity seems to be an
unlikely cause for poor vaccine uptake.
Preterm babies can be eVectively vacci-
nated with BCG at 34–35 weeks of postcon-
ceptional age, the normal time of dis-
charge in a developing country.
(Arch Dis Child Fetal Neonatal Ed 1999;81:F64–F66)
Keywords: BCG; tuberculin test; lymphocyte migration
inhibition test
BCG vaccination is compulsory in 64 countries
and is oYcially recommended in a further 118.
In 10 randomised controlled trials conducted
throughout the world since 1930, the overall
protection aVorded by BCG vaccination has
ranged from 0–80%. BCG vaccination seems
to limit the multiplication and dissemination of
the tubercle bacillus, rather than preventing
infection in someone already exposed to the
disease. This explains the 80–100% protection
aVorded by neonatal BCG vaccination against
tuberculous meningitis reported in several
case–control trials.1–4 In the UK 75 per cent of
cases of tuberculous meningitis occur in
children under 5 years of age who are thus in an
age group that could have been protected by
neonatal BCG vaccination.1
However, there are no guidelines regarding
BCG vaccination in preterm babies who
constitute about 8–10% of all neonates and
who may not be immunocompetent to respond
to BCG antigen. Our previous study had
shown similar seroconversion rates in preterm
babies and term babies following oral polio
vaccination.5 In most studies on the eYcacy of
neonatal BCG vaccination, the preterm infants
were not studied separately. To the best of our
knowledge, there have only been three small
studies conducted on BCG vaccination of pre-
term babies and they have reached conflicting
conclusions.6–8
This study aimed to determine whether
BCG vaccination given early to preterm babies
at 34–35 weeks is as eVective as when given late
at 38–40 weeks of postconceptional age.
Methods
Ninety one preterm, appropriate for gestational
age (AGA) babies of <35 weeks, consecutively
born at the All India Institute of Medical
Sciences between December 1995 and March
1997, were included in the trial. Critically ill
babies, defined as those requiring assisted ven-
tilation or parenteral fluids above two thirds of
their total requirement; babies who underwent
exchange transfusion; twins; babies who re-
ceived immunoglobulins, steroids, INH
prophylaxis; and babies with congenital malfor-
mations, were excluded from the study. Small
for date babies were excluded because our pre-
vious work had shown poor uptake of BCG
vaccine.9
Twenty nine babies were thus excluded and
the remaining 62 were randomly allocated
(block randomisation with permuted blocks)
into two groups after obtaining parental
consent. Babies in group A were vaccinated
early at 34–35 weeks and group B were
vaccinated late at 38–40 weeks of postconcep-
tional age.
The two groups were similar in terms of
gestational age (mean (SD) 33.1(1.1) and 33.0
(1.2) weeks), birthweight (1583 (204) and
1546 (218) g), neonatal problems, socioeco-
nomic status and postnatal weight gain.
Danish 1331 (BCG) manufactured at
Guindy according to the regulations of the
State Serum Institute in Copenhagen, was
administered intradermally in a dose of 0.1 ml.
Tuberculin skin tests were done 6–8 weeks
after vaccination using 0.1 ml of 1 TU PPD RT
23. An induration of more than 5 mm (read
between 48–72 hours after the intradermal
injection) was taken as a positive response.
Both BCG and tuberculin skin tests were
administered and read by the principal author.
Mantoux reading was double checked by an
experienced immunisation nurse.
Arch Dis Child Fetal Neonatal Ed 1999;81:F64–F66F64
Department of
Paediatrics
All India Institute of
Medical Sciences
New Delhi
India
S Thayyil-Sudhan
M Singh
V K Paul
A K Deorari
Clinical Immunology
Division
A Kumar
Correspondence to:
Dr S Thayyil-Sudhan
Department of Paediatrics
Leicester Royal Infirmary
Leicester LE1 5WW
Email: sudlints@aol.com
Accepted 15 February 1999
group.bmj.com on September 11, 2017 - Published by http://fn.bmj.com/Downloaded from 
The lymphocyte migration inhibition test
(LMIT) was done on all the babies, 6–8 weeks
after vaccination. Several studies have shown
good correlation between the in vivo response
measured by LMIT and the in vitro response
measured by tuberculin skin test, following
BCG vaccination. LMIT is reported to be
more sensitive than the tuberculin skin test in
assessing the cell mediated immune response
to BCG vaccine.9–11
Blood anticoagulated with heparin was
mixed with 2% gelatin in phosphate buVered
saline taken in a silicon tube. Cells were
allowed to migrate in Perspex chambers for
16–18 hours in minimal essential medium
(MEM) containing 10% fetal calf serum with
or without the antigen (PPD). A migration
index of less than 0.8 was taken as a positive
response, indicating a cell mediated immune
response to BCG.9–11
Results
One baby in group A died due to intraventricu-
lar haemorrhage and sepsis; the rest completed
the study. There was no significant diVerence
in the incidence of tuberculin conversion, posi-
tive LMIT, or BCG scar among the two groups
(p>0.05).
Ninety per cent of the preterm babies
vaccinated early and 87.1% of those vaccinated
late had a scar or ulcer at the vaccine site (table
1), indicating successful vaccination. Eighty per
cent of the babies in both groups had positive
Mantoux conversion. Positive LMIT was seen in
86.6% of the early vaccinees and 90.2% of the
late vaccinees, indicating a cell mediated im-
mune response to BCG vaccination. Mean
induration after the tuberculin skin test was also
similar, 5.27 mm (SD1.8) in group A and 5.26
mm (SD1.6) in group B. None of the babies had
induration of more than 10 mm (fig 1).
All the babies with scars except one (98.1%)
were positive for LMIT. Of the seven scar
negative babies, three (42.8%) were positive for
LMIT. The tuberculin test and LMIT showed
good correlation (r = 0.84). The tuberculin
skin test showed a high degree of sensitivity and
specificity when the cutoV for a positive Man-
toux reaction was taken as 5 mm, considering
LMIT as the gold standard for immune
response. None of the babies had any compli-
cations following the vaccination. Small axil-
lary lymph nodes (<5 mm) were found in 36%.
Discussion
The study shows similar uptake and cell medi-
ated immune responses against BCG vaccine
in preterm babies vaccinated early at 34 weeks
and late at 38–40 weeks of postconceptional
age. Delaying the age of vaccination did not
seem to improve the conversion rates and
might increase the number of missed vaccina-
tion opportunities. The conversion rates in
preterm babies are similar to those reported
for term neonates.12 13 None of the babies had
lymph nodes of more than 5 mm or suppura-
tion.
Dawadu et al reported a tuberculin conver-
sion rate (induration >5 mm) of 83% in 12
preterm babies vaccinated at birth compared
with 88% conversion rates in eight preterm
babies vaccinated at 38–40 weeks of postcon-
ceptional age.6 The diVerences, however, were
not significant and the findings show that BCG
vaccine can be given eVectively at 34–35 weeks
of postconceptional age in preterm babies.
Small for date babies, those who had respira-
tory distress syndrome, sepsis, jaundice, ap-
noea, and those who had congenital malforma-
tions, were excluded from this study.
In a recent study Sedaghatian and Kardouni
examined the tuberculin response and scar for-
mation following BCG vaccination of preterm
babies at birth.7 The study included 289
preterm babies, but only 70 (24.2%) com-
pleted the study. The only exclusion criteria
was major congenital malformation. Thirty two
per cent of the babies had no BCG scar and
only 20% had tuberculin conversions of more
than 5 mm. The authors therefore concluded
that routine BCG vaccination in preterm
babies was not indicated. Poor follow up and
inclusion of sick and small for date babies
might have influenced the results of their study.
No in vivo tests were used to elicit the cell
mediated immune response in this study.
In their second study Sedaghatian et al com-
pared the tuberculin skin tests and scars
following BCG vaccination in 36 preterm
babies vaccinated at birth (group 1), 16
preterm babies vaccinated at 40 weeks (group
2), and 20 full term babies vaccinated at birth
(group 3). The only exclusion criterion used in
this study was a multiple congenital anomaly.
Thirty three per cent, 25%, and 25%, respec-
tively, of babies in groups 1, 2, and 3 produced
negative Mantoux reactions. BCG scars were
absent in 55%, 44%, and 40%, respectively.
Table 1 Tuberculin conversion, lymphocyte migration test (LMIT), and scar formation
(vaccine uptake) after BCG vaccination of preterm babies
Group A (n=30) Group B (n=31)
p Valuen (%) 95% CI n (%) 95% CI
Positive tuberculin skin test 24 (80.0) 61.4, 92.3 25 (80.7) 62.5, 92.6 *0.8
Positive LMIT 26 (86.6) 69.3, 96.2 28 (90.3) 74.3, 98.0 §0.7
BCG scar 27 (90.0) 73.5, 97.9 27 (87.1) 70.2, 96.4 §1.0
*÷2 test (0.07) with Yates’ correction; §Fisher’s exact test (2 tailed).
Group A: preterm babies vaccinated early at 34–35 weeks of postconceptional age.
Group B: preterm babies vaccinated late at 38–40 weeks of postconceptional age.
Figure 1 Induration diameter of tuberculin skin test in preterm babies studied.
20
18
14
16
12
8
10
6
4
0
2
8–9
Induation following Tuberculin skin test (mm)
N
u
m
b
er
 o
f 
b
ab
ie
s
6–74–50–1 2–3
Group A
Group B
Safety and eVectiveness of BCG vaccination in preterm babies F65
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The diVerences in the Mantoux conversion
rates and BCG scar between the three groups
were not significant (p>0.4). The authors sub-
sequently did a multivariate analysis and found
that birthweight was significantly associated
with tuberculin skin test reaction. It was there-
fore concluded that routine BCG vaccination
at birth of preterm babies of <33 weeks is not
indicated, until further studies are done.8
A Mantoux conversion rate of 81.2 % was
observed in both term neonates and low birth-
weight babies vaccinated at birth in a recent
study by Ferreria et al.12 These conversion rates
are very similar to those in our study.
Correlation between the protection aVorded
by BCG vaccination and tuberculin skin re-
sponses is controversial. However, skin test
responses and in vitro assays of cell mediated
immunity are probably the best surrogates of the
eYcacy of BCG vaccine, currently available.14
Prematurity itself seems to be an unlikely
cause for poor vaccine uptake and cell
mediated immune response. Thus we conclude
that babies born at 34 weeks can be safely vac-
cinated with BCG within days after birth,
which is the time when they are discharged
from hospital in developing countries.
We thank Dr Richard Hancock, Queen’s Hospital, Burton, UK,
for statistical assistance and Mr Gopal Singh for assisting with
laboratory work.
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WHO 1990;68:69–74.
5 Thayyil-Sudhan S, Singh M, Broor S, Xess I, Paul VK,
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6 Dawadu AH. Tuberculin conversion following BCG vacci-
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F66 Thayyil-Sudhan, Kumar, Singh, Paul, Deorari
group.bmj.com on September 11, 2017 - Published by http://fn.bmj.com/Downloaded from 
preterm babies
Safety and effectiveness of BCG vaccination in
and Ashok Kumar Deorari
Sudhin Thayyil-Sudhan, Ashok Kumar, Meharban Singh, Vinod Kumar Paul
doi: 10.1136/fn.81.1.F64
1999 81: F64-F66 Arch Dis Child Fetal Neonatal Ed 
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Safety and effectiveness of BCG vaccination in preterm babies

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