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The Effect of BCG on Mortality Beyond Infancy: 30-Year Follow-Up of a Double-Blind Randomised Placebo-Controlled Trial of BCG Re-Vaccination in Malawi
18 Pages Posted: 16 Oct 2020More...
Background: Trials of BCG to prevent COVID-19 are taking place in adults, some of whom have been previously vaccinated, but evidence of BCG’s beneficial non-specific effects come largely from data on mortality in infants, and from in vitro and animal studies. We assess all-cause mortality following a large BCG re-vaccination trial in Malawi.
Methods: A population-based double-blind randomised trial comparing BCG re-vaccination vs placebo to prevent tuberculosis and leprosy was initiated in Karonga District, Malawi, in 1986-9, in individuals aged 3 months to 75 years. Active follow-up was carried out in northern areas of the district in 1991-94 and in a southern area in 2002-2018 covering 15.8% (7389 individuals) and 12.0% (5616 individuals) of the trial population respectively. Year of death or leaving the area were recorded for those not found. We used survival analysis to estimate all-cause mortality rates.
Findings: There was no difference in mortality rate between the BCG and placebo group in either follow-up, overall or by age group. Mortality rates in the northern areas were 6.6/1000 person years at risk (pyar), 95% confidence interval 5.5-7.8, and 7.0/1000pyar (5.9-8.2) for those who received BCG and placebo, respectively. In the southern area they were 6.3/1000 pyar, (5.5-7.1), and 5.9/1000 pyar, (5.2-6.8), respectively.
Interpretation: We found no evidence of any beneficial effect of BCG re-vaccination on all-cause mortality. The high proportion of deaths attributable to non-infectious causes beyond infancy, and the long time interval since BCG for most deaths, may obscure any benefits.
Funding Statement: The original trial was funded by primarily by the British Leprosy Relief Association (LEPRA), with assistance from the International Federation of Anti-Leprosy Organizations (ILEP), and the Immunology of Leprosy component of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (IMMLEP/TDR), with support of the Malawian Ministry of Health. The later follow-up was funded by The Wellcome Trust There was no specific funding for this analysis.
Declaration of Interests: We declare no competing interests.
Ethics Approval Statement: The trial protocol was approved in 1985 by the Health Sciences Research Committee of the Malawi Ministry of Health, the Standing Committee on Research in Human Subjects of WHO, and the Ethics Committee of the London School of Hygiene & Tropical Medicine. Follow-up of the population has been approved in the context of other studies by the Health Sciences Research Committee of the Malawi Ministry of Health and the Ethics Committee of the London School of Hygiene & Tropical Medicine.
Keywords: BCG, non-specific effects, re-vaccination, Mortality, COVID-19, randomised controlled trial
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