Efficacy of BCG Vaccine in the Prevention of Tuberculosis

A Meta-analysis ReviewBarbara Waldorf

Laura HajarAbby Link

Scott Shatzman (Last names were taken from Gmail - if wrong, my apologies

and please fix)

Background and Public Health Significance

• Highly contagious, airborne disease– High mortality and

morbidity– Responsible for more

adult deaths than any other pathogen

• Declared a global emergency by WHO in 1993

• Predominantly in the developing world– Areas of poverty

• Refugee camps, prisons, etc.– Overcrowded living conditions

• 2 BILLION people worldwide are infected with TB– 1/10 will go to develop the disease– 9.4 million people developed active TB last year (WHO)– Global incidence of TB reached its peak in 2004 (142/100,000)

BCG - Front Line of TB Control• BCG

– Vaccine was created in 1908 and first used in 1921

– Most widely used vaccine in the world

• 3 billion doses given– Only vaccine currently available for

TB• Efficacy

– More effective against disseminated and meningeal disease in youth than pulmonary disease in adults

– Protective against leprosy, meningtitis

• Controversy – Question to overall efficacy– Duration of protective immunity– Impact of age of vaccination on

protection– Efficacy of individual strains of BCG

• Dr. Graham A. Colditz• Published in the Journal

of American Medicine Association (JAMA)– March 2nd, 1994

• Objective was to quantify the efficacy of BCG vaccine against TB– Reviewed 1264 articles

from MEDLINE– 70 articles reviewed in

depth – Analyzed

• 14 prospective trials• 12 case control studies

Summary• BCG vaccination performance in prospective trials

has ranged from possibly detrimental to an 80% protective benefit

• 10 case control studies showed efficacy in preventing TB– However, protection range was from 2%-90%!

• Confidence in BCG was rocked by the Madras trial – BCG vaccine failed to show any benefit against

pulmonary TB– However, still the recommendation of WHO

Unanswered Questions

• Overall efficacy• The duration of protective immunity• How age at vaccination affects protection

• This study undertook a meta-analysis to test the hypothesis that rates of TB are different in BCG-vaccinated and BCG-non-vaccinated control populations– In addition, aimed to derive overall efficacy rates for

BCG vaccination

Methodology • Identification of trials:

– computerized keyword search on MEDLINE using terms BCG vaccine, tuberculosis, human

– contacted experts on BCG vaccination• Inclusion Criteria:

– studies measuring efficacy of BCG vaccination in preventing TB cases and/or death

– studies on prevalence, control, reviews were searched for relevant references

– trials that randomly established concurrent comparison groups receiving and not receiving BCG vaccine

Data Extraction and Validity Scoring

• For Each Study– year of publication - year vaccination began - study design– age range of study population - sample size - location of study– strain and dose of BCG used - route of administration– follow-up time or time since immunization - outcomes measured– efficacy of vaccine

• Studies represent a 60 year time span and reflect changes in medical practice, reporting techniques, and design and conduct of studies

– in trials, scoring system assessed:• method of vaccine assignment to study population• availability for follow-up• equality of surveillance among both study arms• criteria for diagnosis of TB

– preparation of BCG vaccine

• All scoring done a priori of analysis of results

Statistical Analysis• random effect models used to obtain summary estimates of relative risk or odds

ratio from a group of studies, stratified subsets of trials and studies where the outcome, age at vaccination, methods used for diagnosis, or study design defined the stratification

• studies were further divided into three categories based on method of allocation subject to groups: random, alternate, or systematic

• random effects regression model to look at sources of heterogeneity in efficacy of BCG vaccine reported

• results from prospective trials presented as relative risk, odds ratio in case-control

• investigators repeated meta-analysis computations of TB cases from the 13 prospective trials, adding 20 hypothetical trials each equal in size to the single largest trial and each showing no benefit from BCG vaccine. The efficacy of BCG remained statistically significant even with inclusion of these hypothetical trials.

– their findings remained constant

Table 1

Results BCG PE of preventing TB was 51%. RR 0.49 (0.34-0.70) from 13 trials

(random, alternate and systematic allocation)

BCG PE against TB compared to no vaccination was 50% from 10 case-control studies involving 1414 subjects. OR 0.5 (0.39-0.64)

Among 13 prospective trials, geographic latitude and study validity score explained 66% of the between study variance in the trials. With efficacy of BCG vaccination increasing with increased distance from the equator.

The data validity score was the only variable in a random-effects regression model that explained a substantial amount (36%) of heterogeneity.

Analysis of Results

• The clinical trials were published from 1948-1980.

• Data outlier of 1.56, typical RR of cases of TB ranging from 0.20-1.01 in clinical

trials (can skew data)

• 8 out of 13 clinical trial studies had < 50 cases of TB with BCG and without BCG

• 9 out of 13 clinical trials had < 90 cases of TB for data analysis

• Data validity score- assesses for potential bias in study design and ascertainment of

diagnosis. Heterogeneity was found in biases

• Variance in study size for Clinical Trials: 262-17,6782 Case Control: 282-1,847

• Differences unclear between the case and control groups in Case-Control Studies