International Journal of Infectious Diseases 121 (2022) 113–119

Contents lists available at ScienceDirect

International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

Effectiveness of Bacillus Calmette-Guérin vaccination against severe

childhood tuberculosis in China: a case-based, multicenter
retrospective study
Qiong Liao 1,2,#, Yangming Zheng 3,#, Yanchun Wang 5,#, Leping Ye 3,4,#, Xiaomei Liu 5,#,
Weiwei Jiao 6,#, Yang Liu 1,2, Yu Zhu 1,2, Jihang Jia 1,2, Lin Sun 6,∗, Adong Shen 6,7,∗,
Chaomin Wan 1,2,∗∗
1
Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu, People’s Republic of China
2
Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, China
3
Department of Pediatric Respiratory Medicine, The Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou
325027, China
4
Department of Pediatrics, Peking University First Hospital, Beijing, China
5
Department of Infection Diseases, Kunming Children’s Hospital, Kunming, China
6
Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics (Capital Medical University), Beijing Key
Laboratory of Pediatric Respiratory Infection Diseases, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National
Clinical Research Center for Respiratory Diseases,National Center for Children’s Health, Beijing, China
7
Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, China

a r t i c l e i n f o a b s t r a c t

Article history: Background: Evidence varies regarding the efficacy of Bacillus Calmette-Guérin (BCG) vaccine. Data on
Received 9 November 2021 protection by BCG vaccination against severe tuberculosis (TB) among children in China remain unclear.
Revised 12 March 2022
Methods: We conducted a case-based, multicenter retrospective study at three children’s hospitals in
Accepted 10 April 2022
China. Sociological factors affecting BCG vaccination and risk factors associated with disease types were
analyzed using a multivariable model.
Key words: Results: A total 1701 children with active TB were enrolled. Children who were younger, female, residing
Bacillus Calmette-Guérin in a rural area, living in the western regions, and with no BCG vaccination history were at higher risk
severe tuberculosis of developing severe TB. Children with a BCG scar had significantly lower risk for severe TB (odds ratio
tuberculous meningitis
[OR] 0.59, 95% confidence interval [CI] 0.51–0.67). Children with no BCG scar but who were vaccinated at
effectiveness
birth still had lower risk of severe TB types, such as tuberculous meningitis (OR 0.88, 95% CI 0.80–0.97)
children
and miliary TB (OR 0.77, 95% CI 0.69–0.87).
Conclusions: Neonatal BCG vaccination could be an effective means to control TB. In the absence of a
new, more effective TB vaccine, our results lend support to continued use of the BCG vaccine in China.
© 2022 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious
Diseases.
This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)

Tuberculosis (TB) accounts for the highest global burden among developed TB globally and 1.4 million people died. Children carry
infectious diseases. In 2019, approximately 10 million individuals nearly 10% of the global TB disease burden (Global tuberculosis re-
port, 2020). Owing to their immature immune system, children in-
fected with Mycobacterium tuberculosis (MTB) are at much higher
∗ risk for developing active TB, especially severe types of disease in-
Corresponding to Pro. Lin Sun and Adong Shen at No. 56 Nanlishi Road, Xicheng
District, Beijing, China. cluding tuberculous meningitis (TBM) and miliary TB. Therefore,
∗∗
Corresponding to Pro. Chaomin Wan at No.20, 3rd Section of Renmin South effective prevention strategies against the progression of this dis-
Road, Chengdu, China. ease are critical for TB control in children. As the only TB vaccine
E-mail addresses: chinatka@163.com (L. Sun), shenad16@hotmail.com (A. Shen), licensed for use in humans, the current coverage of the Bacillus
wcm0220@126.com (C. Wan).
#
Calmette-Guérin (BCG) vaccine is generally high (McShane et al.,
These authors contributed equally to this study. Author order was determined
by contributions to the study.

https://doi.org/10.1016/j.ijid.2022.04.023
1201-9712/© 2022 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Q. Liao, Y. Zheng, Y. Wang et al.
2012, Lahey and Fordham von Reyn, 2011), with roughly 100 mil-
lion doses given to infants every year.
The evidence varies for BCG vaccine efficacy, according to ef-
ficacy trials and epidemiological studies conducted over several
decades. The heterogeneity in vaccine effectiveness results from in-
fluencing factors such as characteristics of the host and the envi-
ronment (McShane et al., 2012, Palmer and Long, 1996). It has been
reported that BCG protection against TB ranges from no evidence
of protection to an average of 80% protection (Mangtani et al.,
2014). High estimates of efficacy have been observed for infant
BCG vaccination against severe forms of TB (Trunz et al., 2006,
Rodrigues et al., 1993, Colditz et al., 1995). With one of the highest
TB burdens worldwide, China initiated a neonatal BCG immuniza-
tion program in 1986, reaching an average of 99% vaccination rate
in 2019. However, data about further protection of the BCG vaccine
against severe TB among children in China remain unclear.
Until now, all related studies have been designed to report the
efficacy of BCG vaccination in preventing TB among population-
based cohorts, comparing BCG vaccination with no vaccination.
Large-scale passive follow-up is needed for these studies to trace
and identify participants who subsequently develop TB. Compared
with this, a hospital-based case investigation is easier to conduct.
Each year, a large number of children with active TB are admit-
ted to the respiratory and infectious disease departments of chil-
dren’s hospitals throughout China. The pediatric patient popula-
tion at these hospitals offers a unique opportunity to explore the
efficacy of vaccination. Therefore, we performed a hospital-based
study at three children’s hospitals in China and evaluated the ef-
fectiveness of neonatal BCG vaccination in a pediatric population
of patients with TB.
Methods
Study design and participants
Between January 1, 2002 and December 31, 2018, we performed
a multicenter retrospective study at three children’s hospitals in
China: West China Women’s and Children’s Hospital, Yuying Chil-
dren’s Hospital, and Kunming Children’s Hospital. The prevalence
of TB and the rates of BCG vaccination vary in different areas of
China. West China Women’s and Children’s Hospital and Kunming
Children’s Hospital are located in western China, and Yuying Chil-
dren’s Hospital is located in eastern China.
All children aged 0–18 years old who were diagnosed with ac-
tive TB at any of the three study sites were eligible to be enrolled
in the study. Only patients with complete clinical data were in-
cluded.
Procedures
Sociodemographic and clinical information were collected by
two trained interviewers using data collection tables. Data included
age, sex, ethnic origin, birthplace, and current residence (continu-
ous residence for 6 months or longer). Past medical history was
also collected, including preterm or term birth, history of reported
TB disease, history of close contact with a patient who had active
TB, BCG vaccination, and presence of a BCG scar.
Diagnosis of pediatric TB was mainly based on the guidelines
of the Chinese Medical Association (Subspecialty Group of Respi-
ratory Diseases, Society of Pediatrics, Chinese Medical Association;
Editorial Board, 2006). Patients with exclusively intrathoracic in-
volvement (ie, confined to the lung parenchyma, pleura, and in-
trathoracic lymph nodes) were classified as having pulmonary TB.
Patients with extrapulmonary TB were those in whom disease was
found in organs or tissues outside the thorax and included patients
114
International Journal of Infectious Diseases 121 (2022) 113–119
who also had pulmonary involvement. TBM, miliary TB, and dis-
seminated TB were defined as severe forms of TB. Information of
previous BCG vaccination was recorded, according to vaccination
cards. The presence of a BCG scar was determined by visual exam-
ination of the arms by an experienced clinician.
Statistical analyses
All statistical analyses were conducted using SPSS version 22.0
(SPSS Inc., Chicago, IL, USA). The chi-square test was used to com-
pare differences among independent groups. Variables with a sig-
nificant impact on chi-square tests were entered stepwise into a
multivariable model using the forward conditional method. Trend
analysis between age and disease rate was done using Spearman
test. All statistical hypothesis tests were two-sided, and P values
less than 0.05 were considered to be statistically significant.
The protective efficacy of BCG vaccination against severe TB was
estimated using the formula (1 – rate ratio [RR]) × 100%, as in pre-
vious studies (Pereira et al., 2012, Nguipdop-Djomo et al., 2016),
and was redefined in the present study. We estimated the RRs of
TB by comparing the percentage of severe TB in vaccinated chil-
dren with that in unvaccinated children.
Results
Study population
Between January 1, 2002 and December 31, 2018, we enrolled
1701 children with active TB (median age 7.63 years; SD 5.14 years)
in this multicenter study. Clinical characteristics of the study pop-
ulation are shown in Table 1. Overall, 59.7% of the children were
male and 34.8% were < 5 years old. A total 61.3% participants came
from the western part of China, and 70.2% lived in rural areas. The
distributions of residential area and ethnic origin differed signif-
icantly across hospitals. We found that 68.8% of participants had
a recorded history of BCG vaccination and 20.9% reported having
close contact with a patient who had active TB. A total of 1258
(74.0%) participants had a valid tuberculin skin test result, and 391
(23.0%) of participants were tested by interferon gamma release as-
say.
Risk factors
Sociological factors affecting BCG vaccination were analyzed for
enrolled participants. Factors significantly associated with no his-
tory of BCG vaccination were minority nationality, residing in a ru-
ral area, and living in western China (Table 2).
To confirm the efficacy of the BCG vaccine against severe child-
hood TB, risk factors that were associated with different types of
diseases were further analyzed. The results showed that children
who were younger, minority nationality, resident in a rural area,
living in western China, and those with no history of BCG vacci-
nation were at higher risk of developing severe types of active TB
(Table 3).
Efficacy
Among the 1171 children with a history of BCG vaccination,
1035 (88.4%) were observed to have a BCG scar on their arm, indi-
cating successful neonatal vaccination. When children were further
grouped according to BCG vaccination status, we found that chil-
dren with no BCG scar but who were vaccinated at birth still had
a lower risk of severe types of active TB, with an odds ratio (OR)
of 0.55 (95% confidence interval [CI] 0.37–0.83). Children with suc-
cessful BCG vaccination had even lower risk, with an OR value of
0.37 (95% CI 0.29–0.47) (Table 4).
Q. Liao, Y. Zheng, Y. Wang et al. International Journal of Infectious Diseases 121 (2022) 113–119

Table 1
Characteristics of pediatric tuberculosis patients from three referral hospitals in China.

West China Women’s

Total (n=1701), Yuying Children’s and Children’s Hospital Kunming Children’s
Characteristic N (%) Hospital (n=698), N (%) (n=695), N (%) Hospital (n=308), N (%) P value

Age group, y
<1 180 (10.6) 68 (9.7) 60 (8.6) 52 (16.9) <0.001
1–4 412 (24.2) 157 (22.5) 169 (24.3) 86 (27.9)
5–12 764 (44.9) 243 (34.8) 370 (53.2) 151 (49.0)
13–18 345 (20.3) 230 (33.0) 96 (13.8) 19 (6.2)
Gender
Male 1015 (59.7) 418 (59.9) 414 (59.6) 183 (59.4) 0.988
Female 686 (40.3) 280 (40.1) 281 (40.4) 125 (40.6)
Ethnic origin
Han 1111 (65.3) 695 (99.6) 325 (46.8) 91 (29.5) <0.001
Minority 590 (34.7) 3 (0.4) 370 (53.2) 217 (70.5)
Residence area
City 181 (10.6) 108 (15.5) 56 (10.7) 17 (5.5) <0.001
Town 326 (19.2) 169 (24.2) 115 (21.9) 42 (13.6)
Rural 1194 (70.2) 421 (60.3) 524 (67.4) 249 (80.8)
District
Eastern 659 (38.7) 655(93.8) 4 (0.6) 0(0) <0.001
Western 1042 (61.3) 43(6.2) 691 (99.4) 308(100.0)
BCG vaccination history
Yes 1171 (68.8) 631 (90.4) 321 (46.2) 219 (71.1) <0.001
No 369 (21.7) 44 (6.3) 260 (37.4) 65 (21.1)
No record 161 (9.5) 23 (3.3) 114 (16.4) 24 (7.8)
Presence of BCG scar
Yes 1035 (60.8) 617 (88.4) 312 (44.9) 106 (34.4) <0.001
No 619 (36.4) 77 (11.0) 349 (50.2) 193 (62.7)
No record 47 (2.8) 4 (0.6) 34 (4.9) 9 (2.9)
TB type
PTB 771 (45.3) 421 (60.3) 223 (32.1) 127 (41.2) <0.001
EPTB 930 (54.7) 277 (39.7) 472 (67.9) 181 (58.8)
Severity of TB
Severe 618 (36.3) 169 (24.2) 330 (47.5) 119 (38.6) <0.001
Other 1083 (63.7) 529 (75.8) 365 (52.5) 189 (61.4)
TB contact history
Yes 355 (20.9) 86 (12.3) 181 (26.0) 88 (28.6) <0.001
No 1336 (78.5) 610 (87.4) 509 (73.2) 217 (70.5)
No record 10 (0.6) 2 (0.3) 5 (0.7) 3 (1.0)

BCG = Bacillus Calmette-Guérin; TB = tuberculosis.

Table 2
Risk factors associated with BCG vaccination in children with active tuberculosis.

characteristics BCG vaccinated (n=1171), N (%) BCG unvaccinated (n=369), N (%) p value Adjusted p value Adjusted OR (95% CI)

Age group, y
<1 130 (11.1) 40 (10.8) <0.001 0.236 Reference
1–4 291 (24.9) 85 (23.0) 1.37 (0.81–2.33)
5–12 469 (40.1) 196 (53.1) 0.98 (0.63–1.53)
13–18 281 (24.0) 48 (13.0) 1.30 (0.87–1.95)
Gender
Male 708 (60.5) 229 (62.1) 0.583 0.42 Reference
Female 463 (39.5) 140 (37.9) 0.89 (0.68–1.18)
Race
Han 1028 (87.8) 161 (43.6) <0.001 <0.001 Reference
Minority 143 (12.2) 208 (56.4) 4.75 (3.52–6.42)
Residence area
City 163 (13.9) 16 (4.3) <0.001 0.001 Reference
Town 259 (22.1) 45 (12.2) 1.30 (0.68–2.49)
Rural 749 (64.0) 308 (83.5) 2.22 (1.25–3.93)
District
Eastern 600 (51.2) 38(10.3) <0.001 <0.001 Reference
Western 571 (48.8) 331(89.7) 4.13 (2.79–6.10)

BCG = Bacillus Calmette-Guérin.

Protection of the BCG vaccine for children of different ages is
shown in Figure 1. Among vaccinated children, the percentage of
severe TB cases was lower than that among unvaccinated children
in each age subgroup. Around 51.7% (249/482) of TBM cases and
63.5% (80/126) of miliary TB cases occurred in children younger
than 5 years old. With increased age, we observed a more signifi-
cant reduction of risk in children with older age than in those with
younger age; the P trend for severe TB, TBM, miliary TB, and ex-
trapulmonary TB were all <0.001.
Among all children with active TB, the BCG vaccine showed
effectiveness of 38.7% against miliary TB and 38.1% against TBM
(Figure 2). The vaccine effectiveness was lowest in children aged
2–4 years. BCG vaccine effectiveness against severe TB was 11.7%
in children aged 2–4 years.

115
Q. Liao, Y. Zheng, Y. Wang et al. International Journal of Infectious Diseases 121 (2022) 113–119

Table 3
Odds ratio of severe types of active tuberculosis in children by BCG vaccination and other demographic characteristics.

characteristics Nonsevere TB Severe TB (n=618), N (%)∗ TBM (n=482), N (%)∗ Miliary TB (n=126), N (%)∗
(n=1083), N (%) # #
N (%) Adjusted OR (95% CI) N (%) Adjusted OR (95% CI) N (%) Adjusted OR# (95% CI)

Age group, y
<1 86 (7.9) 94 (15.2) Reference 69 (14.3) Reference 39 (31.0) Reference
1–4 208 (19.2) 204 (33.0) 0.87 (0.61–1.25) 180 (37.3) 1.07 (0.73–1.58) 41 (32.5) 0.41 (0.24–0.71)
5–12 504 (46.5) 260 (42.1) 0.41 (0.29–0.57) 196 (40.7) 0.42 (0.29–0.61) 34 (27.0) 0.13 (0.08–0.24)
13–18 285 (26.3) 60 (9.7) 0.22 (0.15–0.34) 37 (7.7) 0.18 (0.11–0.30) 12 (9.5) 0.12 (0.06–0.24)
Gender
Male 657 (60.7) 358 (57.9) Reference 280 (58.1) Reference 67 (53.2) Reference
Female 426 (39.3) 260 (42.1) 1.20 (0.97–1.50) 202 (41.9) 1.21 (0.95–1.53) 59 (46.8) 1.60 (1.07–2.39)
Race
Han 842 (77.8) 395 (63.9) Reference 314 (65.1) Reference 91 (72.2) Reference
Minority 241 (22.2) 223 (36.1) 1.31 (1.01–1.69) 168 (34.9) 0.90 (0.66–1.23) 35 (27.8) 0.75 (0.45–1.25)
Residence area
City 133 (12.3) 48 (7.8) Reference 35 (7.3) Reference 15 (11.9) Reference
Town 238 (22.0) 88 (14.2) 0.92 (0.60–1.42) 68 (14.1) 0.91 (0.56–1.48) 18 (14.3) 0.60 (0.27–1.30)
Rural 712 (65.7) 482 (78.0) 1.37 (1.01–1.99) 379 (78.6) 1.40 (0.91–2.13) 93 (73.8) 0.82 (0.43–1.56)
District
Eastern 506 (46.7) 153 (24.8) Reference 127 (26.3) Reference 25 (19.8) Reference
Western 577 (53.3) 465 (75.2) 1.98 (1.53–2.57) 355 (73.7) 1.75 (1.31–2.32) 101 (80.2) 2.77 (1.65–4.64)
BCG vaccination history$
Yes 823 (82.3) 348 (64.4) Reference 274 (65.9) Reference 72 (60.5) Reference
No 177 (17.7) 192 (35.6) 2.02 (1.52–2.67) 142 (34.1) 1.99 (1.46–2.70) 47 (39.5) 2.56 (1.58–4.14)
TB contact history$
Yes 208 (19.3) 147 (24.0) Reference 111 (23.3) Reference 47 (37.3) Reference
No 871 (80.7) 465 (76.0) 1.18 (0.90–1.53) 366 (76.7) 1.17 (0.88–1.55) 79 (62.7) 0.71 (0.47-1.08)

BCG= Bacillus Calmette-Guérin; TB = tuberculosis; TBM = tuberculosis meningitis.

∗
: Adjusted OR was calculated based on the comparison with nonsevere tuberculosis subgroup. # :Controlling for variables with p<0.05 in univariate analysis. $ : Children
without record information were excluded.

Discussion The rate of BCG vaccination showed an uneven distribution in

To the best of our knowledge, this is the largest hospital-based
study to explore BCG vaccination effectiveness in children who de-
veloped active TB. The main findings of our study revealed that the
rate of BCG vaccination in China varies among children according
to residential area and ethnic origin. BCG vaccination significantly
reduced the progression to severe TB among children with active
TB, even in children who had been vaccinated but had no BCG scar.
this study. Children with minority nationality, residents in rural ar-
eas, and those living in western China were more likely to have
a lower vaccination rate. The observed vaccination status is con-
sistent with data reported in nationwide epidemiological investi-
gations conducted in 20 0 0, which included children younger than
14 years (National Technical Steering Group of the Epidemiologi-
cal Sampling Survey for Tuberculosis, 2002). The BCG vaccination
status showed that the positive rate in children with a BCG scar

116
Q. Liao, Y. Zheng, Y. Wang et al.
was 94%, 77%, and 60% in children from cities, towns, and rural
areas, respectively. In addition, the distribution of BCG vaccina-
tion matched the incidence of TB in China. Districts with lower
BCG vaccinate rates have higher TB incidence. According to data
from five population-based nationwide epidemiological investiga-
tions conducted from 1979–2010, the active and smear-positive
prevalence of pulmonary TB is higher in central and western China
than in eastern China; the prevalence is also higher in rural areas
than in cities (National Technical Steering Group of the Epidemio-
logical Sampling Survey for Tuberculosis, 2002, Technical Guidance
Group of the Fifth National TB Epidemiological Survey, 2012). Al-
though nearly 99% of newborns are vaccinated with BCG in China,
those born in remote, economically underdeveloped regions, or
in areas with large concentrations of ethnic minorities, often had
lower vaccine coverage. According to Chinese policy, all newborn
infants should receive the BCG vaccine at birth in the hospital
where they are born. However, it is difficult to provide immu-
nization management for children born in private health clinics. A
more effective management system is therefore needed for chil-
dren residing in vulnerable areas, including promotion of neona-
tal immunization programs and increasing awareness of the danger
of TB, as well as providing follow-up BCG vaccination for unvacci-
nated children at younger ages.
Confirmation of the target population is critical to adequately
manage immunization against TB. Data from the present study
showed that children who were younger, residing in rural areas or
in western China, and those who had no history of BCG vaccina-
tion history had higher risk of severe types of active TB. A previ-
ous investigation at our hospital between 2002 and 2010 that in-
cluded 1212 children with active TB suggested that more severe
cases of TB occurred in patients younger than 1 year and those
from rural areas (Wu et al., 2012). Children with severe TB are
more likely to have sequelae or to die, and the cost of treatment
of severe TB is much higher than that of pulmonary TB. Studies
have concluded that BCG is a cost-effective intervention against se-
vere childhood TB, one that is only slightly less cost-effective than
the treatment of active disease with short-course chemotherapy,
especially in southeast Asia, Africa, and the western Pacific region
where TB infection rates are high (Trunz et al., 2006). Thus, BCG
vaccination of high-risk populations can potentially contribute to
the vision of “zero tuberculosis deaths in children.”
Our results confirmed neonatal BCG vaccination protection
against severe forms of TB, including TBM and miliary TB. Scar
formation after vaccination is normally used to evaluate the up-
take and effectiveness of the vaccine. The inspection and counting
of post-BCG vaccination scars is thought to be an important in-
dex in BCG vaccination programs (Dam et al., 1976). Many studies
estimating vaccine effectiveness use the presence or absence of a
scar to differentiate between vaccinated and unvaccinated individ-
117
International Journal of Infectious Diseases 121 (2022) 113–119
uals in the study population (Pereira et al., 2012). Interestingly, we
found that even individuals with no scar formation still had protec-
tion against severe TB. Children without a BCG scar but who were
vaccinated at birth had lower risk of developing severe TB than
unvaccinated children. Data from previous studies indicate that al-
though 10% of children fail to develop a scar after BCG vaccina-
tion, the absence of a scar does not mean that the child did not
benefit from the vaccine because most children develop a positive
cell-mediated immune response (Dhanawade et al., 2015). How-
ever, our results still support the viewpoint that children with a
BCG scar are at lowest risk for severe types of active TB. A multisite
prospective cohort study in four prefectural cities of China found
that among children vaccinated with BCG, infants with a scar had
a higher percentage of positive tuberculin skin test reactions than
those without a scar, indicating that a BCG scar represents a satis-
factory immune response to vaccination (Pang et al., 2015).
Follow-up of participants in cohort trials showed that BCG pro-
tection can last up to 15 years or longer (Abubakar et al., 2013,
Aronson et al., 2004). However, follow-up studies on the effec-
tiveness of neonatal vaccination are lacking. A cluster randomized
study showed that first vaccination of school-aged children re-
sulted in a reduction of TB incidence, and the vaccine effectiveness
increased with time since vaccination; during nine years of follow-
up, the RR in the first four and a half years was higher than that in
the last four and a half years (Pereira et al., 2012). In the present
study, when we classified children by age, we found a higher
prevalence of severe TB among unvaccinated participants versus
vaccinated participants in each age subgroup. Children younger
than 5 years are more likely to develop severe TB, and the RR de-
clines with increased age. Protection that is associated with age
can be explained by gradually maturing immunologic function. Af-
ter infection with MTB, immune cells in older children can more
effectively control the pathogen and can quickly block blood trans-
mission of tuberculosis. However, the exact role of BCG vaccination
in protection is unclear.
Our results raise important questions with respect to re-
evaluating the value of BCG vaccination in preventing severe TB in
children. China stopped BCG revaccination in 1995; hence, all chil-
dren in this study were vaccinated once at birth. Two large-sample
cluster randomized trials evaluating the prevention efficacy of BCG
revaccination found that a second vaccination does not provide any
protection against TB (Rodrigues et al., 2005, Karonga Prevention
Trial Group, 1996). Efforts have also been made to develop new
TB vaccine candidates. A new TB vaccine, MVA85A, that was de-
signed to enhance the protective efficacy of BCG, failed to provide
protection against TB or MTB infection in infants (Tameris et al.,
2013). Several adjuvanted protein subunit vaccines developed as
BCG-booster vaccines were investigated in Phase 2 trials. A sub-
unit vaccine consisting of a recombinant fusion protein (H4) and
Q. Liao, Y. Zheng, Y. Wang et al. International Journal of Infectious Diseases 121 (2022) 113–119

IC31 adjuvant (H4:IC31) showed efficacy in preventing MTB infec-

tion ranging from 3.0%–50.2% (Nemes et al., 2018). A Phase 2b trial
of the M72/AS01E TB vaccine in Kenya, South Africa, and Zambia

: OR was calculated based on the comparison with PTB subgroup. $ : Children without record information were excluded.
0.70(0.47–1.05)
0.41(0.32–0.53)
provided 54.0% protection in adults infected with MTB against ac-

OR (95% CI)
tive pulmonary TB disease; however, data for children are lacking

Reference
(Van Der Meeren et al., 2018). Thus, much remains to be done to-
ward the development of a novel vaccine that can serve to replace
or boost the BCG vaccine.
Neonatal BCG vaccination could be an effective additional

248 (31.0)

472 (59.0)
80 (10.0)
means for controlling TB in children. Consideration should be given
EPTB∗∗

N (%)

to children at higher risk of severe TB. Management should be im-

proved for children who did not receive neonatal vaccination in
western and rural China. In the absence of a new, more effective
121 (16.4)

563 (76.1)

TB vaccine, our results support the continued use of BCG in China.

56 (7.6)
PTB,

(%)
N

Declaration of Competing Interest

0.53 (0.27–1.05)
0.31(0.20–0.46)

The authors declare that they have no known competing finan-

OR (95% CI)

cial interests or personal relationships that could have appeared to

Reference

influence the work reported in this paper.

Funding source
Miliary TB∗

47 (44.8)

52 (49.5)
6 (5.7)
N (%)

The study was supported by a grant from the National Science

and Technology Major Project of China (2018ZX10103001-003) and
Research Development Project of Sichuan Provincial Science and
0.55 (0.36–0.87)
0.41(0.31–0.53)

Technology Department (2020YFS0042).

OR (95% CI)

Reference

Author contributions

Lin Sun, Adong Shen, and Chaomin Wan conceptualized and

designed the study, drafted the initial manuscript, and reviewed
139 (33.7)

236 (57.3)
37 (9.0)

and revised the manuscript. Qiong Liao, Yangming Zheng, Yanchun

N (%)
TBM∗

Wang, Leping Ye, Xiaomei Liu, Yang Liu, Yu Zhu, Jihang Jia, and
Weiwei Jiao enrolled the subjects and collected data. Lin Sun and
Weiwei Jiao analyzed the data. All authors approved the final
0.55 (0.37–0.83)
0.37(0.29–0.47)

manuscript as submitted and agree to be accountable for all as-

The association between BCG vaccinated status and disease types of tuberculosis in children

∗∗
OR (95% CI)

pects of the work.

: OR was calculated based on the comparison with nonsevere tuberculosis subgroup.
Reference

BCG= Bacillus Calmette-Guérin; TB = tuberculosis; TBM = tuberculosis meningitis.

Ethical Statement
Severe TB, N (%)∗

Not applicable.
192 (35.6)

297 (55.0)
51 (9.4)
N (%)

Reference

Abubakar I, Pimpin L, Ariti C, et al. Systematic review and meta-analysis of the cur-
177 (17.7)

738 (73.9)
Nonsevere

rent evidence on the duration of protection by bacillus Calmette-Guerin vacci-

85 (8.5)

nation against tuberculosis. Health Technol Assess 2013;17:1–372 v-vi.

Aronson NE, Santosham M, Comstock GW, et al. Long-term efficacy of BCG vac-
TB,

(%)
N

cine in American Indians and Alaska natives: a 60-year follow-up study. JAMA
2004;291:2086–91.
BCG vaccinated but scar positive (n=1035)

Colditz GA, Berkey CS, Mosteller F, et al. The efficacy of bacillus Calmette-Guerin
BCG vaccinated but scar negative (n=136)

vaccination of newborns and infants in the prevention of tuberculosis: meta–

analyses of the published literature. Pediatrics 1995;96:29–35.
Dam GT, Toman K, Hitze KL, Guld J. Present knowledge of immunization against
tuberculosis. Bull World Hlth Org 1976;54:255–69.
Dhanawade SS, Kumbhar SG, Gore AD, Patil VN. Scar formation and tuberculin con-
BCG unvaccinated (n=369)

version following BCG vaccination in infants: A prospective cohort study. J Fam-

ily Med Prim Care 2015;4:384–7.
Global tuberculosis report 2020. Geneva: World Health Organization, 2020.
Karonga Prevention Trial Group. Randomised controlled trial of single BCG, repeated
BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevention
characteristics$

of leprosy and tuberculosis in Malawi. Lancet 1996;348:17–24.

Lahey T, Fordham von Reyn C. Mycobacterium bovis BCG and new vaccines against
tuberculosis. In: Schlossberg D, editor. Tuberculosis and nontuberculous my-
cobacterial infections. Washington, DC: ASM Press; 2011. p. 162–81.
Table 4

Mangtani P, Abubakar I, Ariti C, et al. Protection by BCG vaccine against tuber-

culosis: a systematic review of randomized controlled trials. Clin Infect Dis
∗

2014;58:470–80.
McShane H, Jacobs WR, Fine PE, et al. BCG: myths, realities, and the need for alter-
native vaccine strategies. Tuberculosis 2012;92:283–8.

118
Q. Liao, Y. Zheng, Y. Wang et al.
National Technical Steering Group of the Epidemiological Sampling Survey for Tu-
berculosis; Office of the Nationwide Epidemiological Sampling Survey for Tuber-
culosis. Report on nationwide random survey for the epidemiology of tubercu-
losis in 20 0 0. Chin J Antituberculosis 2002;24:65–108.
Nemes E, Geldenhuys H, Rozot V, et al. Prevention of M. tuberculosis Infection with
H4:IC31 Vaccine or BCG Revaccination. N Engl J Med 2018;379:138–49.
Nguipdop-Djomo P, Heldal E, Rodrigues LC, Abubakar I, Mangtani P. Duration of
BCG protection against tuberculosis and change in effectiveness with time since
vaccination in Norway: a retrospective population-based cohort study. Lancet
Infect Dis 2016;16(2):219–26.
Palmer CE, Long MW. Effects of infection with atypical mycobacteria on BCG vacci-
nation and tuberculosis. Am Rev Respir Dis 1996;94:553–68.
Pang Y, Kang W, Zhao A, et al. The effect of bacille Calmette-Guérin vaccination at
birth on immune response in China. Vaccine 2015;33:209–13.
Pereira SM, Barreto ML, Pilger D, et al. Effectiveness and cost- effectiveness of first
BCG vaccination against tuberculosis in school-age children without previous
tuberculin test (BCG-REVAC trial): a cluster- randomised trial. Lancet Infect Dis
2012;12:300–6.
Rodrigues LC, Diwan VK, Wheeler JG. Protective effect of BCG against tuber-
culous meningitis and miliary tuberculosis: a meta-analysis. Int J Epidemiol
1993;22:1154–8.
119
International Journal of Infectious Diseases 121 (2022) 113–119
Rodrigues LC, Pereira SM, Cunha SS, et al. Effect of BCG revaccination on incidence
of tuberculosis in school-aged children in Brazil: the BCG-REVAC cluster-ran-
domised trial. Lancet 2005;366:1290–5.
Subspecialty Group of Respiratory Diseases, Society of Pediatrics, Chinese Medical
Association; Editorial Board, Chinese Journal of Pediatrics. Diagnostic standards
and therapeutic recommendations for pulmonary tuberculosis in children. [in
Chinese]. Zhonghua Er Ke Za Zhi 2006;44(4):249–51.
Tameris MD, Hatherill M, Landry BS, et al. Safety and efficacy of MVA85A, a new
tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised,
placebo-controlled phase 2b trial. Lancet 2013;381:1021–8.
Technical Guidance Group of the Fifth National TB Epidemiological Survey, the Of-
fice of the Fifth National TB Epidemiological Survey. The fifth national tubercu-
losis epidemiological survey in 2010. Chin J Antituberc 2012;34:485–508.
Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuberculous menin-
gitis and miliary tuberculosis worldwide: a metaanalysis and assessment of
cost-effectiveness. Lancet 2006;367:1173–80.
Van Der Meeren O, Hatherill M, Nduba V, et al. Phase 2b Controlled Trial of
M72/AS01E Vaccine to Prevent Tuberculosis. N Engl J Med 2018.
Wu XR, Yin QQ, Jiao AX, et al. Pediatric tuberculosis at Beijing Children’s Hospital:
2002–2010. Pediatrics 2012;130:e1433–40.