Trial of Two Strains of BCG

Morbidity Clinical Trial

— BCGSTRAIN  

Official title:

Evaluating the Effect of Different BCG Strains on Early Life Hospital Admissions in Guinea-Bissau: A Randomised Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02447536
• Other study ID #: BCGSTRAIN
• Status: Completed
• Phase: Phase 4
• Start date: December 8, 2014
• Est. completion date: May 1, 2018

Study information

• Verified date: December 2020
• Source: Bandim Health Project
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The investigators aim to conduct a randomised controlled trial comparing two Bacille Calmette-Guérin (BCG) strains currently used in Guinea-Bissau, the Danish and the Russian, in terms of prevention of neonatal and early life morbidity and mortality, immune responses and adverse events related to BCG vaccination. The primary outcome will be hospital admissions within 6 weeks of age.

Description:

BACKGROUND At the Bandim Health Project (www.bandim.org) in Guinea-Bissau, we observed that Bacille Calmette-Guérin (BCG) vaccination at birth is associated with survival benefits which cannot be explained by prevention of tuberculosis (TB), which is rare during the first year of life. There is mounting evidence that the beneficial effects of BCG on neonatal mortality stems from non-specific beneficial immune training, also termed heterologous immunity. This way, BCG immunisation possibly confers enhanced protection against a broad range of severe infections such as pneumonia and septicemia.

In addition, observational studies from Guinea-Bissau suggest that BCG-vaccinated children who produced a scar upon immunisation have significantly better survival than BCG-vaccinated children who did not produce a scar. The pattern is the same with regard to PPD (tuberculin) skin test. While correct BCG-vaccination technique is undoubtedly important for scarring, several studies have shown that the strain of BCG might be important as well.

Globally, BCG coverage exceeds 90%, making BCG the most widely used vaccine in the world. According to UNICEF, the annual demand for the BCG vaccine was 130 million doses in 2013. Several different vaccine strains are being used, yet few studies have compared the different strains. However, several animal and human studies have shown that these genetically diverse vaccine strains induce different protective efficacy against TB, risk of adverse events and susceptibility to anti-TB drugs. Recently, a large observational study based in Uganda showed that there were significant differences between BCG strains concerning the response to specific mycobacteria and non-specific immune responses. In particular, BCG-Denmark was associated with a much higher rate of scarring (93%) than BCG-Russia (52%), but also a higher rate of adverse events in terms of ulcers and abscesses (1.8% versus 0.3%).

OBJECTIVE We aim to compare the effect of two strains of BCG (BCG-Denmark, BCG-Russia) provided at birth to children born at the National Hospital Simão Mendes (HNSM) on subsequent hospitalisations. Furthermore, mortality in the first 6 weeks and adverse events at 2 and 6 months of age will be reported for all children, and BCG scar frequency (2 and 6 months) and PPD response (6 months) will be reported for a proportion of the infants.

METHODS The study will be conducted by the Bandim Health Project (BHP). The BHP maintains a health and demographic surveillance system (HDSS) in 6 districts of the capital in Guinea-Bissau covering approximately 102,000 inhabitants. All houses in the HDSS are visited monthly and all pregnancies and births are registered.

Study participants will be enrolled at the National Hospital and followed up through the HDSS and by telephone interviews as well as through hospital records. The study will be individually randomised, with 1:1 randomisation between the two strains (BCG-Denmark, BCG-Russia). During a two year inclusion period, we expect to be able to include at least 12,000 children, i.e. 6,000 in each BCG strain group. Of these, around 25% will reside within the HDSS.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12006
• Est. completion date: May 1, 2018
• Est. primary completion date: November 24, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

Newborn infants at the HNSM maternity ward.

Exclusion Criteria:

Infants included in another randomized trial of BCG. Infants with a severe congenital abnormality.

Related Conditions & MeSH terms

• Bacille Calmette-Guérin
• Morbidity

Intervention

Biological:
• BCG-Denmark 1331 (Statens Serum Institute)
See above
• BCG-Russia-I (Serum Institute of India)
See above

Locations

Country	Name	City	State
Guinea-Bissau	Bandim Health Project, Apartado 861	Bissau

Sponsors (2)

Lead Sponsor	Collaborator
Bandim Health Project	Statens Serum Institut

Country where clinical trial is conducted

Guinea-Bissau, 

References & Publications (16)

Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM, Stensballe L, Diness BR, Lausch KR, Lund N, Biering-Sørensen S, Whittle H, Benn CS. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis. 2011 Jul 15;204(2):245-52. doi: 10.1093/infdis/jir240. — View Citation

Aaby P, Whittle H, Benn CS. Vaccine programmes must consider their effect on general resistance. BMJ. 2012 Jun 14;344:e3769. doi: 10.1136/bmj.e3769. — View Citation

Anderson EJ, Webb EL, Mawa PA, Kizza M, Lyadda N, Nampijja M, Elliott AM. The influence of BCG vaccine strain on mycobacteria-specific and non-specific immune responses in a prospective cohort of infants in Uganda. Vaccine. 2012 Mar 9;30(12):2083-9. doi: 10.1016/j.vaccine.2012.01.053. Epub 2012 Jan 31. — View Citation

Behr MA. BCG--different strains, different vaccines? Lancet Infect Dis. 2002 Feb;2(2):86-92. Review. — View Citation

Behr MA. Correlation between BCG genomics and protective efficacy. Scand J Infect Dis. 2001;33(4):249-52. Review. — View Citation

Biai S, Rodrigues A, Nielsen J, Sodemann M, Aaby P. Vaccination status and sequence of vaccinations as risk factors for hospitalisation among outpatients in a high mortality country. Vaccine. 2011 May 9;29(20):3662-9. doi: 10.1016/j.vaccine.2011.03.016. Epub 2011 Apr 6. — View Citation

Biering-Sørensen S, Aaby P, Napirna BM, Roth A, Ravn H, Rodrigues A, Whittle H, Benn CS. Small randomized trial among low-birth-weight children receiving bacillus Calmette-Guérin vaccination at first health center contact. Pediatr Infect Dis J. 2012 Mar;31(3):306-8. doi: 10.1097/INF.0b013e3182458289. — View Citation

Garly ML, Martins CL, Balé C, Baldé MA, Hedegaard KL, Gustafson P, Lisse IM, Whittle HC, Aaby P. BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG? Vaccine. 2003 Jun 20;21(21-22):2782-90. — View Citation

Lawn JE, Cousens S, Zupan J; Lancet Neonatal Survival Steering Team. 4 million neonatal deaths: when? Where? Why? Lancet. 2005 Mar 5-11;365(9462):891-900. — View Citation

Penfold S, Willey BA, Schellenberg J. Newborn care behaviours and neonatal survival: evidence from sub-Saharan Africa. Trop Med Int Health. 2013 Nov;18(11):1294-316. doi: 10.1111/tmi.12193. Epub 2013 Sep 24. Review. — View Citation

Ritz N, Curtis N. Mapping the global use of different BCG vaccine strains. Tuberculosis (Edinb). 2009 Jul;89(4):248-51. doi: 10.1016/j.tube.2009.03.002. Epub 2009 Jun 18. — View Citation

Ritz N, Hanekom WA, Robins-Browne R, Britton WJ, Curtis N. Influence of BCG vaccine strain on the immune response and protection against tuberculosis. FEMS Microbiol Rev. 2008 Aug;32(5):821-41. doi: 10.1111/j.1574-6976.2008.00118.x. Epub 2008 Jul 9. Review. — View Citation

Roth A, Gustafson P, Nhaga A, Djana Q, Poulsen A, Garly ML, Jensen H, Sodemann M, Rodriques A, Aaby P. BCG vaccination scar associated with better childhood survival in Guinea-Bissau. Int J Epidemiol. 2005 Jun;34(3):540-7. Epub 2005 Jan 19. — View Citation

Roth A, Sodemann M, Jensen H, Poulsen A, Gustafson P, Weise C, Gomes J, Djana Q, Jakobsen M, Garly ML, Rodrigues A, Aaby P. Tuberculin reaction, BCG scar, and lower female mortality. Epidemiology. 2006 Sep;17(5):562-8. — View Citation

Schaltz-Buchholzer F, Bjerregaard-Andersen M, Øland CB, Golding C, Stjernholm EB, Monteiro I, Aaby P, Benn CS. Early Vaccination With Bacille Calmette-Guérin-Denmark or BCG-Japan Versus BCG-Russia to Healthy Newborns in Guinea-Bissau: A Randomized Control — View Citation

Wardlaw T, You D, Newby H, Anthony D, Chopra M. Child survival: a message of hope but a call for renewed commitment in UNICEF report. Reprod Health. 2013 Dec 11;10:64. doi: 10.1186/1742-4755-10-64. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hospital admission		6 weeks after birth
Secondary	Mortality	Reported exclusively for a subgroup of infants with regular house visits	6 weeks
Secondary	BCG scar frequency	Reported exclusively for a subgroup of infants with regular house visits	6 months
Secondary	PPD (tuberculin response)	Reported exclusively for a subgroup of infants with regular house visits	6 months
Secondary	Adverse events (abscesses/ulcers)	Adverse events to the vaccines will be evaluated for a subgroup of infants with regular house visits	6 months
Secondary	Hospital admission during neonatal period		4 weeks