Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis
BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g4643 (Published 05 August 2014) Cite this as: BMJ 2014;349:g4643
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I am heartened by the findings of the above study. The study underlines what is already known about the efficacy of BCG vaccination. However, the authors also found a protective efficacy of 19% against TB infection among vaccinated children after exposure to TB compared with BCG unvaccinated children. This appears to be new evidence in relation to the efficacy of BCG vaccination and warrants further investigation.
However, there are a number of questions that may affect the reliability of the findings. I seek the views of the authors with regard to these questions:
1) The presence or absence of infection was determined by IGRA testing in the meta-analysis. The accuracy of IGRA testing in detecting TB infection in young children remains unclear.
2) The timing of IGRA testing following exposure to TB may affect the result. Did the studies indicate at what point IGRA testing took place after exposure?
3) The nature and degree of proximity between the index case and close contacts are likely to vary considerably.
4) Variables related to individual contacts such as health and nutritional status. Was anything, for example, known about the vitamin D levels among vaccinated/unvaccinated individuals?
Competing interests: No competing interests
Rees et al in their response assert that BCG should never be given without 2 negative PCR tests for HIV in an exposed infant. This is not in keeping with the latest guidance from the British HIV association (1) who suggest that where the risk of transmission is low (as in the majority of cases in the UK) and the risk of TB is high (as in many families affected by HIV) then the BCG should be given at birth. This is an important change in practice that should have been included in their response.
1 BHIVA guidelines for the management of HIV infection in pregnant women 2012 (2014 update)
Competing interests: No competing interests
Dear Editors,
We thank Drs. Turner, Fernandes, Dharmshaktu and Rees for their interest in our findings that BCG vaccines in different countries and populations protect against development of tuberculosis infection in children with Mycobacterium tuberculosis exposure.(1) The observation that tuberculin sensitised individuals are less protected in our review of BCG and active TB(2,3) further argues for a role in protecting against infection.
Dr. Turner and colleagues(4) do not accept the conclusion that BCG prevents M. tuberculosis infection without a valid mechanism and instead propose an alternative hypothesis for an apparent effect. Our work presents the consistent epidemiological finding of a protective effect of BCG against TB infection rather than attempting to speculate on a mechanism of action for this protective effect which was out with the stated objectives of our meta-analysis. Absence of a valid mechanism is not usually a basis for rejecting conclusions from consistently observed findings.(5) Indeed, the protective effect of BCG against TB disease is not in doubt even though a mechanism (and a correlate) of protection remain elusive after decades of investigation.(6) Notwithstanding, we believe that the development of new vaccines for tuberculosis can only progress as we undertake more research to disentangle the mechanism of action of BCG vaccines, including their effects on both innate and adaptive immune responses.(7) Turner et al’s proposed alternative explanation, based on the fact that antigens used in IGRA are absent from BCG, is undermined by the observation of BCG’s protective effect against TB infection when using the tuberculin skin test (TST) instead of IGRA as a marker of infection(8)(9) (Soysal et al, Lancet 2005 and Pulickal et al. Indian Pediatr 2007). Purified protein derivative comprises hundreds of M. tuberculosis antigens shared by BCG so that TST results in these studies could not be subject to ‘original antigenic sin’.
Dr Dharmshaktu(10) speculates about the potential therapeutic role of BCG vaccines, for which evidence is increasing and which merits further investigation.(11)(12) We agree with Dr Fernandes(13) that BCG has an important role in the prevention of leprosy and with Phillipa Rees and colleagues(14) that children should be assessed for contraindications to BCG and other vaccines prior to immunisation
I Abubakar, S Sridhar, M Eisenhut, A Roy, R J Harris, L C Rodrigues, P Mangtani, I Adetifa, A Lalvani,
References
1. Roy A, Eisenhut M, Harris RJ, Rodrigues LC, Sridhar S, Habermann S, et al. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. BMJ. 2014;349:g4643.
2. Abubakar I, Pimpin L, Ariti C, Beynon R, Mangtani P, Sterne J a. C, et al. Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guérin vaccination against tuberculosis. Health Technol Assess Winch Engl. 2013 Sep;17(37):1–372, v–vi.
3. Mangtani P, Abubakar I, Ariti C, Beynon R, Pimpin L, Fine PEM, et al. Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials. Clin Infect Dis Off Publ Infect Dis Soc Am. 2014 Feb;58(4):470–80.
4. Turner R, Tweed C, Bothamley G. Re: Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. BMJ. http://www.bmj.com/content/349/bmj.g4643.
5. Parascandola M, Weed DL. Causation in epidemiology. J Epidemiol Community Health. 2001 Dec;55(12):905–12.
6. Kagina BMN, Abel B, Scriba TJ, Hughes EJ, Keyser A, Soares A, et al. Specific T cell frequency and cytokine expression profile do not correlate with protection against tuberculosis after bacillus Calmette-Guérin vaccination of newborns. Am J Respir Crit Care Med. 2010 Oct 15;182(8):1073–9.
7. Lalvani A, Sridhar S, von Reyn CF. Tuberculosis vaccines: time to reset the paradigm? Thorax. 2013 Dec;68(12):1092–4.
8. Soysal A, Millington KA, Bakir M, Dosanjh D, Aslan Y, Deeks JJ, et al. Effect of BCG vaccination on risk of Mycobacterium tuberculosis infection in children with household tuberculosis contact: a prospective community-based study. Lancet. 2005 Oct 22;366(9495):1443–51.
9. Pulickal AS, Fernandez GVJ. Comparison of the prevalence of tuberculosis infection in BCG vaccinated versus non-vaccinated school age children 10545. Indian Pediatr. 2007;44(5):344–7.
10. Dharmshaktu G. BCG vaccination – After prevention, the therapeutic role needs to be validated. BMJ. http://www.bmj.com/content/349/bmj.g4643/rr/762464.
11. Jeremiah K, Praygod G, Faurholt-Jepsen D, Range N, Andersen AB, Grewal HM, et al. BCG vaccination status may predict sputum conversion in patients with pulmonary tuberculosis: a new consideration for an old vaccine? Thorax. 2010 Dec;65(12):1072–6.
12. Lalvani A, Sridhar S. BCG vaccination: 90 years on and still so much to learn .. Thorax. 2010 Dec;65(12):1036–8.
13. Fernandes P. The benefits of BCG vaccination are not confined to protection against Mycobacterium tuberculosis. BMJ. http://www.bmj.com/content/349/bmj.g4643/rr/762491.
14. Rees P, Evans H, Panesar S, Llewelyn M, Edwards A. Contraindicated BCG vaccination of “at risk” infants. BMJ. http://www.bmj.com/content/349/bmj.g4643/rr/762808.
Competing interests: No competing interests
We welcome the findings of Roy et al. regarding the effectiveness of the BCG vaccine in preventing Mycobacterium tuberculosis (TB) infection in immunocompetent children.(1) However, we urge health care professionals responsible for the prescribing and administration of BCG vaccinations to be mindful of significant contraindications that pose risks to immunocompromised patients.(2)
Our characterisation of primary care-related paediatric safety incidents from the England and Wales National Reporting and Learning System (NRLS) includes 1790 vaccine-related incidents from 2005-2013.(3) Although under-reporting is commonly cited as the Achilles’ heel of the NRLS, incidents involving unsafe delivery of the BCG vaccine feature frequently.(4) Our exploration has identified 99 reports of BCG-related incidents in children at risk of TB exposure– either by living in or having family members from areas with a high prevalence of TB. A recurring theme is the administration of BCG vaccines to infants of HIV-positive mothers in whom full assessment of their HIV status had not been completed.(5) There is a risk of disseminated BCG disease in children infected with HIV.(2) Public Health England’s “Green Book” provides clear guidance on this, recommending that BCG should only be administered after two “appropriately timed negative postnatal PCR blood tests for HIV infection”. (6) Poor communication between health services–maternity care, child health and general practice– is frequently described as contributing to such incidents. Typically, infants are sent appointments by child health services as a result of deficiencies or discrepancies between maternal and child health records. This creates a situation whereby healthcare professionals are unaware of a child’s vulnerability.
Vaccine errors remain a threat to patient care.(7) Contraindications to BCG must be explicitly referenced within the unified forms and there is a need for better linkage of maternal and child health records that are accessible in primary and secondary care settings. We caution healthcare professionals not to rely solely on medical records but to consider – double-check – and fully explore with parents (including use of translation services if needed) the child’s suitability for the vaccine prior to administration.
References
1. Roy A, Eisenhut M, Harris RJ, Rodrigues LC, Sridhar S, Habermann S, et al. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. BMJ. 2014(349):g4643.
2. Hesseling AC, Marais BJ, Gie RP, Schaaf HS, Fine PE, Godfrey-Faussett P, et al. The risk of disseminated Bacille Calmette-Guerin (BCG) disease in HIV-infected children. Vaccine. 2007;25(1):14-8.
3. National Institute for Health Research. Characterising the nature of primary care patient safety incident reports in England and Wales: mixed methods study. Available from: http://www.nets.nihr.ac.uk/projects/hsdr/1264118.
4. Vincent C, Aylin P, Franklin BD, Holmes A, Iskander S, Jacklin A, et al. Is health care getting safer? BMJ. 337:a2426.
5. Public Health England. Tuberculosis. In: Immunisation against infectious disease [Internet]. 2003 [cited 13th Aug 2014]: [391-409]. Available from: www.gov.uk/government/publications/tuberculosis-the-green-book-chapter-32.
6. Public Health England. Contraindications and special considerations: the green book, chapter 6. In: Immunisation against infectious disease [Internet]. 2013 [cited 14th Aug 2014]: [41-48]. Available from: https://www.gov.uk/government/publications/contraindications-and-special...
7. Derrough TF, Kitchin NR. Occurrence of adverse events following inadvertent administration of childhood vaccines. Vaccine. 2002;21(1-2):53-9.
Competing interests: ACS and AE are co-chief investigators of a NIHR HS&DR grant to characterise patient safety incident reports in primary care. PR is a research assistant employed to work on the study. AJ has no conflicts of interest. PH is the former Associate Director of the National Patient Safety Agency responsible for the development of recommendations from patient safety incident reports received by the National Reporting and Learning System.
Roy et al show that BCG vaccination protects against both M tuberculosis infection and progression of infection to disease. However, it is important to recognise that vaccination with BCG confers additional benefits to those discussed by Roy: namely, protection against M leprae and, perhaps, other non-tuberculous mycobacterial species. Whilst the incidence and prevalence of leprosy has declined markedly over the last 10 years it remains a significant public health challenge, with over 200,000 new cases per year [1]. A meta-analysis shows that BCG vaccination seems to give an average protective effect against leprosy of 26%, albeit with significant heterogeneity between studies [2]. Similarly, BCG vaccination of leprosy contacts is also protective, both with [3] and without [4] additional chemo-prophylaxis with rifampicin. BCG vaccination may also provide some protection against a third mycobacterial infection: Buruli ulcer, caused by M ulcerans [5]. Although the protective effects of BCG vaccination against non-tuberculous mycobacteria are limited, and may not provide a primary reason for widespread use, these additional benefits do constitute a secondary argument for BCG vaccination in addition to the main aim of preventing M tuberculosis infection and disease.
References
[1] World Health Organization. Global leprosy situation, 2012. Weekly Epidemiological Record, 2012; 87:317-328
[2] Maninder Singh Setia, Craig Steinmaus, Christine S Ho, et al. The role of BCG in prevention of leprosy: a meta-analysis. Lancet Infectious Diseases, 2006; 6:162-170
[3] Ron P Schuring, Jan Hendrik Richardus, David Pahan, et al. Protective effect of the combination BCG vaccination and rifampicin prophylaxis in leprosy prevention. Vaccine, 2009, 27:7125-7128
[4] NC Duppre, LAB Camacho, SS da Cunha, et al. Effectiveness of BCG vaccination among leprosy contacts: a cohort study. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2008; 102:631-638
[5] van der Werf T S, Stienstra Y, Johnson R C et al. Mycobacterium ulcerans disease. Bulletin of the World Health Organization, 2005, 83: 785-791
Competing interests: No competing interests
It is heartening to read this article as it reaffirms the effectiveness of BCG vaccination against tubercular infection. It has been an effective tool in the fight against this deadly disease especially in developing countries like India. India has well adopted the BCG shots in its preventive health programme and has witnessed a positive outcome over the years. The improvement, however, does not seem to markedly reflect in the grass root level as the prevalence of the disease is still humungous with morbidity and mortality a common affair. This country with its huge burden and complex interplay of population, poverty, malnutrition, illiteracy and hygiene issues serves as an ideal milieu for Mycobacterium tuberculosis to flourish. A sizeable number of new cases as well as those who default treatment and refractory or resistant cases keep on increasing despite all measures.
The promising preventive role of BCG vaccination has rekindled hope that it might also be used for therapeutic purposes. There is still a paucity of good quality literature support in this regard but the rationale is not misplaced. Many workers in India have included BCG vaccination as part of the treatment as an immune-modulatory therapy for refractory cases.1,2 They report encouraging results but a good level 1 study is required to authenticate their findings.3
More than anything else, there is an urgent need for better therapeutic agents or regimens in the wake of the insurgence of multi drug or extremely drug resistant (MDR/XDR) cases.
We might witness an outstanding discovery of an adjuvant therapeutic effects of this simple, inexpensive and proven agent.
References –
1. Tuli SM. Tuberculosis of the Skeletal System. 4th ed. New Delhi: JP Brothers Medical Publishers;2010.p.18-30.
2. Arora A, Nadkarni B, Dev G, Chattopadhyaya D, Jain AK, Tuli SM , et al. The use of immunomodulators as an adjunct to anti tuberculous chemotherapy in nonresponsive patients with osteo-articular tuberculosis. J Bone Joint Surg Br 2006;88:264-9.
3. Tuli SM. Preliminary observations on the effect of immunomodulation in multidrug resistant cases of osteoarticular tuberculosis. Indian J Orthop 1999;33:83-5.
Competing interests: No competing interests
The evidence for the protective effect of BCG against primary forms of active tuberculosis is now well established. However, evidence for protection against acquisition of infection with Mycobacterium tuberculosis (Mtb) is much more controversial. Roy et al show that previous BCG infection is associated with a reduced incidence of positive interferon-γ response assay (IGRA) response in children despite risk of exposure to Mtb.[1] Although a positive IGRA response is currently the best surrogate marker for Mtb infection it has limitations, which if overlooked can lead to misinterpretation of data. This is particularly the case in young children.[2]
A positive IGRA response does not confirm the presence of viable Mtb but indicates a previous interaction with Mtb that was sufficient to lead to an adaptive immune response. For BCG to prevent infection it must limit this interaction, either by physically limiting entry of bacilli to the alveoli or by somehow strengthening elements of the innate immune system. The authors do not propose any potential mechanisms by which BCG might do this. Furthermore, it is difficult to see how a vaccine could be effective against active disease, through an influence on the adaptive immune system, whilst simultaneously preventing the interaction with T lymphocytes on initial exposure to Mtb required to produce immunity.
There is an alternative explanation for the finding that previous BCG vaccination reduces IGRA responses following exposure to Mtb, that BCG alters rather than prevents the interaction between Mtb and the adaptive immune system during infection. With BCG vaccination, T-cells will gain a memory for the majority of mycobacterial antigens which are shared with Mtb. However, there would be no memory for ESAT-6, CFP10 and TB7.7, which are present in Mtb but absent in BCG. Thus, when the BCG-vaccinated subject meets Mtb, the secondary and larger immune response is mounted against those antigens which have been previously recognised, but a primary response to the three new antigens is either not mounted or too small to elicit a response in the IGRA. This concept of “original antigenic sin” has been well-demonstrated for serial immune responses to strains of influenza [3] and has also been shown to occur in other mycobacterial species.[4 5]
Research into tuberculosis continues to be hampered by the lack of a gold standard for determining sub-clinical or latent infection with Mtb. We cannot accept the conclusion that BCG prevents Mtb infection without a valid mechanism for how this might occur when there is another explanation for the lack of IGRA responses in children exposed to Mtb.
1. Roy A, Eisenhut M, Harris RJ, et al. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. BMJ 2014;349:g4643.
2. Mack U, Migliori GB, Sester M, et al. LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement. Eur Resp J 2009;33(5):956–73.
3. Kim JH, Skountzou I, Compans R, Jacob J. Original antigenic sin responses to influenza viruses. J Immunol 2009;183(5):3294–301.
4. Bothamley GH. BCG and protection against Mycobacterium tuberculosis infection. Lancet 2006;367(9508):393.
5. Bothamley G, Beck JS, Britton W, Elsaghier A, Ivanyi J. Antibodies to Mycobacterium tuberculosis-specific epitopes in lepromatous leprosy. Clin Exp Immunol 1991;86(3):426–32.
Competing interests: No competing interests
Contraindicated BCG vaccination in “at risk” infants: Authors respond
Dr Daniels clarifies exceptions to the general rule of BCG vaccination of infants at risk of HIV.1 Where an infant is deemed at low risk of HIV at birth, Dr Daniels correctly highlights that BCG could be administered in the hospital setting and that the General Practitioner be informed.2
Our research identified patient safety incidents involving infants who received BCG vaccination in primary care.3 Erroneous administration of BCG vaccine in infants ‘at risk’ of HIV was one example of many BCG-related vaccine incidents reported to the National Reporting and Learning System between 2003-2013. System failures permitting BCG-related incidents–including but not restricted to the examples discussed–were the basis of our recommendations for improvement.
1. Daniels JG. Re: Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-anaysis. BMJ 2014;349:g46. Available from: http://www.bmj.com/content/349/bmj.g4643/rr/764496
2. British HIV association guidelines for the management of HIV infection in pregnant women. 2012 (2014 update). Available from: http://www.bhiva.org/documents/Guidelines/Pregnancy/2012/BHIVA-Pregnancy...
3. Rees P, Evans H, Panesar S, Llewelyn M, Edwards A, Carson-Stevens A. Contraindicated BCG vaccination in “at risk” infants. BMJ 2014;349:g5388. Available from: http://www.bmj.com/content/349/bmj.g5388
Competing interests: AC-S and AE are co-chief investigators of a National Institute for Health Research Health Services and Delivery Research grant to characterise patient safety incident reports in primary care. PR is a research assistant employed to work on the study. HE and ML have no conflicts of interest. SP is a former clinical adviser at the National Patient Safety Agency (2008-10) and an academic clinical fellow at Imperial College London working for the National Reporting and Learning System researc