Research Protocol

By Dr. Noor Ani Ahmad
Corresponding Author Dr. Noor Ani Ahmad
Institute for Public Health, Institute for Public Health, Jln Bangsar, - Malaysia 50590
Submitting Author Dr. Noor Ani Ahmad

Bacillus Calmette- Guerin (BCG), Revacc (BCG), Revaccination and Protection Against Tuberculosis

Ahmad N. Protocol for a Systematic Review: Bacillus Calmette- Guerin (BCG) Revaccination and Protection Against Tuberculosis. WebmedCentral PUBLIC HEALTH 2011;2(11):WMC002535
doi: 10.9754/journal.wmc.2011.002535
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Submitted on: 29 Nov 2011 07:43:14 PM GMT
Published on: 30 Nov 2011 09:40:48 AM GMT


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.


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, 1.2-1.5 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 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.


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.  
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) Routine revaccination irrespective of TB immune status or
ii) Revaccination given for either absence or presence of visible scar following primary vaccination or
iii) 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.
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.
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.
Statistical analysis
If we find any randomized or quasi-randomised controlled trials we will perform meta-analysis 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.


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.


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.


1. Fact sheets No.104: Tuberculosis. http//wwwwhoint\mediacentre\factsheets\fs104\en\ access on 11 October 2011 November 2010
2. Higgins JPT GS: Cochrane handbook for systematic reviews of interventions. West Sussex, England Wiley-Blackwell A John Wiley & Sons 1998.
3. Alison D Grant KMDC: The growing challenge of HIV/AIDS in developing countries. British Medical Bulletin 1998, 54(2):369-381.
4. Tocque K DM, Bellis MA, Spence DPS, Williams CSD: Tuberculosis notifications in England: the relative effects of deprivation and immigration. . Int J Tuberc Lung Dis 1998, 2(3):213-221.
5. Fact sheets, TB Elimination: BCG Vaccine http://wwwcdcgov/tb/publications/factsheets/vaccine/BCGpdf?s_cid=cs_476 access on 11 October 2011 November, 2008.
6. WHO: WHO Weekly Epidemiological Record 2004, 4(79):25-40.
7. Laura C Rodrigues VKD, Jeremy G Wheeler: Protective effect of BCG against tuberculosis meningitis and milliary tuberculosis: A meta-analysis. Int J Epidemiol 1993, 22:1154-1158.
8. Graham A. Colditz TFB, Catherine S. Berkey, Mary E. Wilson, Elisabeth Burdick, Harvey V. Fineberg, Frederick Mosteller.: Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA 1994, 271(9):698-702.
9. Fine. PEM: BCG vaccination against tuberculosis and leprosy. British Medical Bulletin  1998, 44:691-703.
10. Jonathan A C Sterne LCR, Guedes IN.: Does the efficacy of BCG decline with time since vaccination. Int J Tuberc Lung Dis 1998, 2(3):200-207.
11. Reinaldo L Sepulveda-Garese PC, Ricardo U. Sorenson: Case-control study of the efficacy of BCG immunization against pulmonary tuberculosis in young adults in Santiago, Chile. Tubercle and Lung Disease 1993, 73:372-377.
12. Richard J. Sylvester APMvdM, Donald L. Lamm: Intravesical Bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: A meta-analysis of the published results of randomized clinical trials. The Journal of Urology 2002, 168:1964-1970.
13. Andre Lotte W-HO, Poisson N, Engbaek H, Landmann H, Quast U, et al.: Second  IUATLD study on complications induced by intradermal BCG-vaccination. Bull Int Union Tuberc Lung Dis 1988, 63(2):47-59.
14. P D'Arcy Hart IS: BCG and vole bacillus vaccines in the prevention of tuberculosis in adolescence and early adult life. British Medical Journal 1977, 2.
15. World Health Organisation (WHO); Issues relating to the use of BCG in immunization programmes. A discussion document. Geneva. . WHO 1999.
16. Lugosi. L: Theoretical and methodological aspects of BCG vaccine from the discovery of Calmette and Guérin to molecular biology. A review. Tuberculosis Lung Disease 1992, 73(5):252-261.
17. Tala-Heikkila MM TJ, Tala EOJ.: Bacillus Calmette-Guérin Revaccination Questionable with low tuberculosis incidence. Am J Respir Crit Care Med 1998, 157:1324-1327.
18. WHO Weekly Epidemiological Records. . 1995, 70:229-236.
19. Review Manager (RevMan) [Computer program]. Version 5.0. Copenhagen; The Nordic Cochrane Centre. The Cochrane Collaboration 2008.

Source(s) of Funding

This project was funded by the Ministry of Health Malaysia.

Competing Interests

The authors declare that they have no competing interests.


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