PROTOCOL FOR A SYSTEMATIC REVIEW: BACILLUS CALMETTE-GUERIN (BCG)
REVACCINATION AND PROTECTION AGAINST TUBERCULOSIS
Noor Azah Daud1, Jasvindar Kaur1, Noor Ani Ahmad1, Rusidah Selamat1, Ramli Zainal2,
Amirulazman Abu Hassan2, Hazrin Hashim1, Prof Dr Jacqueline Ho3
Abstract
Background: The length of the protective efficacy of BCG vaccine plays an important
role in the establishment of vaccination policies. Revaccination with two or more doses
is supposed to boost up the immunity. However, the effectiveness of BCG revaccination
has been questioned. It was argued that revaccination may increase the rate of tuberculin
conversion but does it result in more sustained reactivity over time.
Method/Design: The research will consist of a systematic review of BCG revaccination.
Randomized, quasi-randomized controlled trials, cohort and case control studies will be
considered for the review involving all age groups. The primary outcomes include the incidence
or prevalence of pulmonary tuberculosis, non-pulmonary tuberculosis, the mortality due to
tuberculosis and all-cause mortality within ten years of vaccination. Secondary outcome
measures are immunity status, adverse reactions (mild or severe form) and cost of the
vaccination. Databases will be searched using a comprehensive four-part search
strategy, and the results exported to a bibliographic database. Two review authors will
independently screen results to identify potentially eligible studies, and will
independently extract data from included studies, with any discrepancies at each stage
settled by a third author. Standardized forms and criteria will be used. A descriptive
analysis of included studies will describe study design, participants, the intervention,
and outcomes. Extracted data will be analyzed using appropriate statistical methods.
Discussion: This review aims to provide comprehensive evidence of the protective
effects of revaccination after primary BCG vaccination in neonatal period and its
adverse effects. This evidence is vital for policy makers in deciding whether BCG
revaccination program should be continued or otherwise.
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Background
Tuberculosis (TB) is a major public health problem worldwide. In 2009, there were an
estimated 8.9-9.9 million incident cases of TB, 12-16 million prevalent cases of TB, 1.21.5 million deaths from TB among HIV negative people and an additional 0.32-0.45
million TB deaths among human immunodeficiency virus (HIV) positive people. The
largest number of new TB cases occurred in the South-East Asian Region, which
accounted for 34% of incident cases globally[1]. Pulmonary TB is the most frequent
clinical form, and is responsible for the transmission of the TB bacillus. Although
prolonged or repeated contact is normally required for infection, a single, brief exposure
of small numbers of bacilli may suffice in highly susceptible individuals. An estimated
annual average of 10-15 persons will contract the infection from one case of infectious
pulmonary TB. Resistance to desiccation makes the organism viable in the environment
for prolonged periods [2].
Although there has been a sharp decrease in the occurrence of TB in most
industrialised countries, its incidence has remained high in regions such as Africa and
Eastern Europe. In general, TB has shown an upward trend in countries with a high
incidence of acquired immune deficiency syndrome (AIDS) [3]. In industrialised
countries, the increase in TB cases has been associated with higher levels of poverty
and social inequalities [4].
The BCG vaccine prepared from a strain of attenuated bovine vaccine was first used to
immunise humans in 1921. Following its introduction into the WHO Expanded Program
on Immunization in 1974, the vaccine soon reached global coverage rates exceeding
80% in countries endemic for TB.
There are several regimes for BCG vaccination such as 1) routine administration to all
newborns, 2) administration to selected newborns at risk, 3) to all adolescents 4) only to
selected high risk groups or when tuberculin negative 5) or it may be given later in life to
those without immunity. Countries with a high endemicity would usually have a policy of
routine administration to all newborns. However, BCG is contraindicated in individuals
with impaired immunity[5].
Immunisation with BCG is thought to reduce hematogenous spread of Mycobacterium
tuberculosis (Mtb) from the site of primary infection. If it occurs, haematogenous spread
may result in serious disease, such as milliary tuberculosis and TB meningitis [6].
Studies of overall efficacy have found statistically significant heterogeneity, against
pulmonary and all forms of tuberculosis [7, 8]
The length of the protective efficacy of the BCG vaccine is important in the
establishment of revaccination policies [7]. Estimates of efficacy against tuberculosis
ranged from negative to more than 90% [9]. Protection provided by BCG vaccine has
been found to have 5-14% annual decrease in relative risk of TB in unvaccinated
compared with vaccinated individuals[10] . An efficacy study using mass vaccination
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among school-leavers revealed that protection decreased from 84% in the first five
years to 59% between ten and 15 years [11].
Revaccination with two or more doses was proposed to boost immunity [10, 12]. It has
be given routinely, to individuals who are tuberculin negative or to those without a
visible BCG scar after the first dose. In many developing countries, systematic
revaccination has been practiced because of doubts about the persistence capacity of
the vaccine when given in the early neonatal period [9]. However, it might have adverse
effects such as accelerated local reactions, regional lymphadenitis, subcutaneous
abscess, osteitis, keloid scarring and disseminated infection [13].
The effectiveness of BCG revaccination has been questioned [14-16]. Previously, the
finding of a negative tuberculin skin test response was considered to indicate the need
for revaccination. It was argued that revaccination may increase the rate of tuberculin
conversion and result in more sustained reactivity over time. However the tuberculin
response is not associated with protective benefit derived from BCG vaccination and
there is no evidence that a waning of tuberculin sensitivity with time equates to a loss of
TB specific immunity [17]. In 1995, WHO recommended that for persons who have
received BCG vaccination, repeat vaccination is not recommended as scientific
evidence does not support this practice [18]. Hence, a systematic review is important to
establish whether revaccination is beneficial or otherwise.
AIMS of the Review
The aim of this systematic review is to evaluate the protective effect of revaccination
after primary BCG vaccination in the neonatal period and its adverse effects.
Methods/Design
Design
The research will consist of a systematic review of BCG revaccination.
Criteria for considering studies
Types of study
We will include randomized and quasi-randomized controlled trials including cluster
randomized controlled trials comparing more than one dose with a single dose given in
infancy.
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Types of population
General population of any age, who had received primary BCG vaccination, irrespective
of the proof of previous vaccination/s.
Types of intervention
BCG revaccination is either:
i)
ii)
iii)
Routine revaccination irrespective of TB immune status or
Revaccination given for either absence or presence of visible scar following
primary vaccination or
Revaccination given following negative Tuberculin Test in patients who had
received primary vaccination.
.
Primary outcome measures
1. The incidence or prevalence of pulmonary tuberculosis within ten year
vaccination
2. The incidence or prevalence of non pulmonary tuberculosis within ten year
vaccination.
3. The mortality rate due to tuberculosis within ten year vaccination.
4. All cause mortality.
Secondary outcome measures
1. Measures of immunity for example by tuberculin skin test.
2. Adverse reactions (mild or severe)
Identification of eligible studies and data extraction
Search strategy
We have designed a four-part search strategy: Firstly, we will search electronic
bibliographic databases for published work (see below for databases to be searched).
Secondly, we will search the grey literature for unpublished work. Thirdly, we will search
trial registers for ongoing and recently completed trials. Finally, we will search reference
lists of published studies and contact authors and e-health research groups to check for
more trials. We will attempt to review articles in all languages. To ensure the review is
reasonably up-to-date at reporting, the searches will be re-run immediately prior to
analysis and further studies retrieved for inclusion.
The databases that will be searched are PubMed (National Library of Medicine) and
CENTRAL.
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Screening and review process
All studies identified through the search process will be exported to a bibliographic
database (EndNote version X4) for duplication and screening. Two review authors will
independently examine the titles, abstracts, and keywords of electronic records for
eligibility according to the inclusion criteria above. Results of this initial screening will be
compared between the two review authors, and full-texts obtained for all potentially
relevant reports of trials. Full-texts of potentially eligible trials will go through a
secondary screening by each reviewer using a screening form based on the inclusion
criteria (Additional file 3) for final inclusion in the review, with disagreements resolved by
discussion with a third author. Reference lists of all eligible trials will be searched for
further eligible trials.
Data extraction
Two authors will independently extract characteristics of each trial using a standardized,
pre-piloted, data extraction form (Additional file 4) and eligibility of candidate studies.
The differences in data extraction will be resolved by discussion with a third author.
Publication authors will be contacted in the case of unclear or missing data.
Analysis
Descriptive analysis
We will describe all studies that meet the inclusion criteria, including:
1. Study design
a. Trial design and quality
b. Data collection methods, modes, and techniques; validity of tools
c. Conflict of interest
2. Participants (intervention and control)
a. Socio-economic and demographic characteristics (e.g. age, ethnicity,
education level)
b. Single or multiple revaccination doses
c. Primary vaccination given in the neonatal period (within one month after
birth) or later.
d. Schedule of revaccination (interval between primary and revaccination).
e. Level of tuberculosis endemicity in study population.
f. Presentations of TB and outcomes.
g. Mode of vaccination (intradermal and subcutaneous administration)
3. Intervention
a. Setting and recruitment methods
4. Outcomes
a. Primary and secondary outcomes as mentioned above.
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Statistical analysis
If we find any randomized or quasi-randomised controlled trials we will perform metaanalysis of the included studies with RevMan 5 [19], using a fixed-effects model, unless
significant statistical heterogeneity is found. For categorical data, we will pool outcome
estimates that are measured using relative risk (RR), risk difference (RD) and number
needed to treat for an additional beneficial outcome for each specific comparison with
their respective 95% confidence intervals [2] For continuous data, we will pool
measures at a similar time point using mean difference (MD) with 95% confidence
interval. Where pooled analyses are not possible we will report the results of the
individual studies separately. We will follow the intention-to-treat principle with our
primary data analyses; the original number of participants initially allocated to each arm
will be used as the denominator.
Discussion
Strengths of this review include clear definitions and inclusion criteria, and a systematic
approach to searching, screening and reviewing studies and extracting data using
standardized forms by at least two researchers at all stages. We propose to cover
multiple databases in our search using a search strategy that emphasizes on sensitivity
to capture all possible types of studies that fulfill our criteria. Although every effort will be
made to locate unpublished trials, our findings may still be vulnerable to selective
reporting. Despite a pre-defined and systematic approach to screening and reviewing,
the study will still involve judgments made by review authors, either of which may lead
to bias. This review aims to provide comprehensive evidence for the protective effect of
revaccination after primary BCG vaccination in neonatal period and its adverse effects.
This will assist the policy makers in reviewing BCG vaccination programme.
Additional material
Additional file 1 Glossary
Additional file 2 Search strategies (word file). Search strategies to be
run in Medline database to identify potentially eligible studies for the
review (The Medline strategy is indicative of strategies to be run in all
specified database).
Additional file 3 Screening form (word file). The form used to identify
eligible studies.
Additional file 4 Data extraction form (Word file). The form used to
extract data from eligible studies.
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Competing interests
The authors declare that they have no competing interests.
Authors' contributions
RS and RZ will independently perform the study selection, NAA and NAD will undertake
screening, reviewing, and data extraction. The differences in data extraction will be
resolved by discussion with a third author (AAH). JK and HH will assess the risk of bias
independently and any disagreement will be evaluated by a third author (RZ). All
authors contributed to the writing or editing of the protocol for publication, and will
contribute to the final report and paper.
Acknowledgements
This project was funded by the Ministry of Health Malaysia. The project was conceived
at the Systematic Review Training Workshops organised by the Institute of Health
System Research, Malaysia. The authors would like to extend their gratitude to the
facilitator, for his assistance in this project.
Author Details
1 Institute
for Public Health, Ministry of Health, Malaysia.
2 Institute
for Health Systems Research, Ministry of Health, Malaysia.
3
Penang Medical College, Malaysia
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