The effect of BCG revaccination on all-cause mortality beyond infancy: 30-year follow-up of a population-based, double-blind, randomised placebo-controlled trial in Malawi.

BACKGROUND: Trials of BCG vaccination to prevent or reduce severity of COVID-19 are taking place in adults, some of whom have been previously vaccinated, but evidence of the beneficial, non-specific effects of BCG come largely from data on mortality in infants and young children, and from in-vitro and animal studies, after a first BCG vaccination. We assess all-cause mortality following a large BCG revaccination trial in Malawi. METHODS: The Karonga Prevention trial was a population-based, double-blind, randomised controlled in Karonga District, northern Malawi, that enrolled participants between January, 1986, and November, 1989. The trial compared BCG (Glaxo-strain) revaccination versus placebo to prevent tuberculosis and leprosy. 46 889 individuals aged 3 months to 75 years were randomly assigned to receive BCG revaccination (n=23 528) or placebo (n=23 361). Here we report mortality since vaccination as recorded during active follow-up in northern areas of the district in 1991-94, and in a demographic surveillance follow-up in the southern area in 2002-18. 7389 individuals who received BCG (n=3746) or placebo (n=3643) lived in the northern follow-up areas, and 5616 individuals who received BCG (n=2798) or placebo (n=2818) lived in the southern area. Year of death or leaving the area were recorded for those not found. We used survival analysis to estimate all-cause mortality. FINDINGS: Follow-up information was available for 3709 (99·0%) BCG recipients and 3612 (99·1%) placebo recipients in the northern areas, and 2449 (87·5%) BCG recipients and 2413 (85·6%) placebo recipients in the southern area. There was no difference in mortality between the BCG and placebo groups in either area, overall or by age group or sex. In the northern area, there were 129 deaths per 19 694 person-years at risk in the BCG group (6·6 deaths per 1000 person-years at risk [95% CI 5·5-7·8]) versus 133 deaths per 19 111 person-years at risk in the placebo group (7·0 deaths per 1000 person-years at risk [95% CI 5·9-8·2]; HR 0·94 [95% CI 0·74-1·20]; p=0·62). In the southern area, there were 241 deaths per 38 399 person-years at risk in the BCG group (6·3 deaths per 1000 person-years at risk [95% CI 5·5-7·1]) versus 230 deaths per 38 676 person-years at risk in the placebo group (5·9 deaths per 1000 person-years at risk [95% CI 5·2-6·8]; HR 1·06 [95% CI 0·88-1·27]; p=0·54). INTERPRETATION: We found little evidence of any beneficial effect of BCG revaccination 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, might obscure any benefits. FUNDING: British Leprosy Relief Association (LEPRA); Wellcome Trust.

PEP4LEP study protocol: integrated skin screening and SDR-PEP administration for leprosy prevention: comparing the effectiveness and feasibility of a community-based intervention to a health centre-based intervention in Ethiopia, Mozambique and Tanzania.

INTRODUCTION: Leprosy, or Hansen's disease, remains a cause of preventable disability. Early detection, treatment and prevention are key to reducing transmission. Post-exposure prophylaxis with single-dose rifampicin (SDR-PEP) reduces the risk of developing leprosy when administered to screened contacts of patients. This has been adopted in the WHO leprosy guidelines. The PEP4LEP study aims to determine the most effective and feasible method of screening people at risk of developing leprosy and administering chemoprophylaxis to contribute to interrupting transmission. METHODS AND ANALYSIS: PEP4LEP is a cluster-randomised implementation trial comparing two interventions of integrated skin screening combined with SDR-PEP distribution to contacts of patients with leprosy in Ethiopia, Mozambique and Tanzania. One intervention is community-based, using skin camps to screen approximately 100 community contacts per leprosy patient, and to administer SDR-PEP when eligible. The other intervention is health centre-based, inviting household contacts of leprosy patients to be screened in a local health centre and subsequently receive SDR-PEP when eligible. The mobile health (mHealth) tool SkinApp will support health workers' capacity in integrated skin screening. The effectiveness of both interventions will be compared by assessing the rate of patients with leprosy detected and case detection delay in months, as well as feasibility in terms of cost-effectiveness and acceptability. ETHICS AND DISSEMINATION: Ethical approval was obtained from the national ethical committees of Ethiopia (MoSHE), Mozambique (CNBS) and Tanzania (NIMR/MoHCDEC). Study results will be published open access in peer-reviewed journals, providing evidence for the implementation of innovative leprosy screening methods and chemoprophylaxis to policymakers. TRIAL REGISTRATION NUMBER: NL7294 (NTR7503).

Wanda Blenska and the program of leprosy treatment in Uganda.

Wanda Blenska (1911-2014), a Polish physician, established a leprosy treatment center in the village of Buluba in Uganda in 1951, which lasted until 1993. Through her efforts, the village for lepers in Buluba, established in 1934, which had previously been a place of isolation conducted by the Little Sisters of St. Francis in Uganda, became such an important leprosy treatment and research center that eventually the facility was able to cooperate with similar centers in India and South Africa. It then became affiliated with research institutes in London and Amsterdam; the Borstel Research Institute near Hamburg, Germany; and the World Health Organization. Blenska developed a working relationship with the government of Uganda and contributed to changes in the government provision of health care for lepers by creating a network of leprosy treatment stations throughout the country. Through her efforts, public health education and leprosy prophylaxis became available for thousands of people, effectively changing the national attitude toward this disease. In 1994, one of the buildings of the St. Francis hospital complex in Buluba was named in her honor (The Wanda Blenska Training Centre).

Bacille Calmette Guérin (BCG) and new TB vaccines: Specific, cross-mycobacterial and off-target effects.

The Bacille Calmette Guérin (BCG) vaccine was developed over a century ago and has become one of the most used vaccines without undergoing a modern vaccine development life cycle. Despite this, the vaccine has protected many millions from severe and disseminated forms of tuberculosis (TB). In addition, BCG has cross-mycobacterial effects against non-tuberculous mycobacteria and off-target (also called non-specific or heterologous) effects against other infections and diseases. More recently, BCG's effects on innate immunity suggest it might improve the immune response against viral respiratory infections including SARS-CoV-2. New TB vaccines, developed over the last 30 years, show promise, particularly in prevention of progression to disease from TB infection in young adults. The role of BCG in the context of new TB vaccines remains uncertain as most participants included in trials have been previously BCG immunised. BCG replacement vaccines are in efficacy trials and these may also have off-target effects.