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.

Avoiding COVID-19 complications with diabetic patients could be achieved by multi-dose Bacillus Calmette-Guérin vaccine: a case study of beta cells regeneration.

Diabetes mellitus (DM) is one of the major risk factors for COVID-19 complications as it is one of the chronic immune-compromising conditions especially if patients have uncontrolled diabetes, poor HbA1c and/or irregular blood glucose levels. Diabetic patients' mortality rates with COVID-19 are higher than those of cardiovascular or cancer patients. Recently, Bacillus Calmette-Guérin (BCG) vaccine has shown successful results in reversing diabetes in both rats and clinical trials based on different mechanisms from aerobic glycolysis to beta cells regeneration. BCG is a multi-face vaccine that has been used extensively in protection from tuberculosis (TB) and leprosy and has been repositioned for treatment of bladder cancer, diabetes and multiple sclerosis. Recently, COVID-19 epidemiological studies confirmed that universal BCG vaccination reduced morbidity and mortality in certain geographical areas. Countries without universal policies of BCG vaccination (Italy, Nederland, USA) have been more severely affected compared to countries with universal and long-standing BCG policies that have shown low numbers of reported COVID-19 cases. Some countries have started clinical trials that included a single dose BCG vaccine as prophylaxis from COVID-19 or an attempt to minimize its side effects. This proposed research aims to use BCG vaccine as a double-edged weapon countering both COVID-19 and diabetes, not only as protection but also as therapeutic vaccination. The work includes a case study of regenerated pancreatic beta cells based on improved C-peptide and PCPRI laboratory findings after BCG vaccination for a 9 year old patient. The patient was re-vaccinated based on a negative tuberculin test and no scar at the site of injection of the 1st BCG vaccination at birth. The authors suggest and invite the scientific community to take into consideration the concept of direct BCG re-vaccination (after 4 weeks) because of the reported gene expressions and exaggerated innate immunity consequently. As the diabetic MODY-5 patient (mutation of HNF1B, Val2Leu) was on low dose Riomet® while eliminating insulin gradually, a simple analytical method for metformin assay was recommended to ensure its concentration before use as it is not approved yet by the Egyptian QC labs.

The safety of influenza vaccine in clinically cured leprosy patients in China.

BACKGROUND: Leprosy is an infectious disease caused by the bacterium Mycobacterium leprae. Influenza vaccine is an important influenza prevention strategy and the preparations used display good safety and tolerability profiles. But the safety of applying influenza vaccine on the clinical cured leprosy patients is unclear. METHODS: We conducted an observational clinical study, in Wuhan between November 15, 2016 and March 1, 2017. Two groups of participants ≥50 years of age received a 0.5 ml dose of the inactivated split-virion trivalent influenza vaccine and a follow-up 28 days observation of any solicited and unsolicited adverse events. RESULTS: A total of 134 subjects were included in the study. The total rate of reactogenicity was 5.4% [2/37] in leprosy group and 15.5% [15/ 97] in control group, the difference of reactogenicity between two groups was not significant (p = 0.1522). For solicited injection-sites adverse events (AEs), 12.4% [12/ 97] participants in the control group reported of itching, pain, erythema, swelling or induration, and no participants in leprosy group reported of any solicited injection-sites AEs. For solicited systemic AEs, 7.2% [7 / 97] participants in the control group reported of fever, malaise or headache, and 2.7% [1 / 37] participants in the leprosy group reported of fever, statistic result showed that the difference was not significant (p = 0.4438). Unsolicited AEs was reported by one male aged 76, 4 hours after vaccination administration, his plantar ulcer area began bleeding. All AEs were grade 1 or grade 2, and no recurrence of lepra reaction, AEs leading to early withdrawal from the study, or deaths were reported in this study. CONCLUSIONS: To our knowledge, the present study is the first clinical study to evaluate the safety of influenza vaccine in clinically cured leprosy patients. We concluded that clinically cured leprosy patients are relatively safe for influenza vaccine. More importantly, our study make a positive and scientific efforts to eradicate discrimination on leprosy. In our study, we described a patient with plantar ulcer undergoing bleeding for 4 hours after vaccine administration. Based on evidence we have, we interpret that this adverse event may probably associated with vaccine, and patients with ulcer and leprosy need intensive attention after vaccines administration.

rBCG30-induced immunity and cross-protection against Mycobacterium leprae challenge are enhanced by boosting with the Mycobacterium tuberculosis 30-kilodalton antigen 85B.

Leprosy remains a major global health problem and typically occurs in regions in which tuberculosis is endemic. Vaccines are needed that protect against both infections and do so better than the suboptimal Mycobacterium bovis BCG vaccine. Here, we evaluated rBCG30, a vaccine previously demonstrated to induce protection superior to that of BCG against Mycobacterium tuberculosis and Mycobacterium bovis challenge in animal models, for efficacy against Mycobacterium leprae challenge in a murine model of leprosy. rBCG30 overexpresses the M. tuberculosis 30-kDa major secretory protein antigen 85B, which is 85% homologous with the M. leprae homolog (r30ML). Mice were sham immunized or immunized intradermally with BCG or rBCG30 and challenged 2.5 months later by injection of viable M. leprae into each hind footpad. After 7 months, vaccine efficacy was assessed by enumerating the M. leprae bacteria per footpad. Both BCG and rBCG30 induced significant protection against M. leprae challenge. In the one experiment in which a comparison between BCG and rBCG30 was feasible, rBCG30 induced significantly greater protection than did BCG. Immunization of mice with purified M. tuberculosis or M. leprae antigen 85B also induced protection against M. leprae challenge but less so than BCG or rBCG30. Notably, boosting rBCG30 with M. tuberculosis antigen 85B significantly enhanced r30ML-specific immune responses, substantially more so than boosting BCG, and significantly augmented protection against M. leprae challenge. Thus, rBCG30, a vaccine that induces improved protection against M. tuberculosis, induces cross-protection against M. leprae that is comparable or potentially superior to that induced by BCG, and boosting rBCG30 with antigen 85B further enhances immune responses and protective efficacy.

BCG vaccination and leprosy protection: review of current evidence and status of BCG in leprosy control.

The bacillus Calmette-Guérin (BCG) vaccine, initially developed to provide protection against TB, also protects against leprosy; and the magnitude of this effect varies. Previous meta-analyses did not provide a summary estimate of the efficacy due to the heterogeneity of the results. We conducted a meta-analysis of published data including recently published studies (up to June 2009) to determine the efficacy of BCG protection on leprosy and to investigate whether age at vaccination, clinical form, number of doses, type of study, the latitude of study area and year of publication influence the degree of efficacy and explain the variation. In the light of the results, we argue for more emphasis on the role of BCG vaccination in leprosy control and research.

The antipoverty vaccines.

The neglected tropical diseases represent a group of parasitic and bacterial diseases, occurring primarily in rural areas or impoverished urban areas of developing countries. Because of their chronic and stigmatizing character and their impact on child development, pregnancy outcomes, and worker productivity, the neglected tropical diseases are considered poverty-promoting conditions. Through the activities of public-private partnerships, first or second-generation recombinant vaccines for three of these conditions--hookworm, leishmaniasis, and schistosomiasis, have undergone early development and clinical testing. However, through the acquisition of extensive bioinformatics information or animal model testing for several other neglected tropical diseases pathogens, it is possible to consider new generation vaccines as well for amebiasis, Buruli ulcer, Chagas disease, Chlamydia infections (including trachoma), leprosy, leptospirosis, and the treponematoses. Early development of such antipoverty vaccines will require the establishment of product development public-private partnerships and partnerships with innovative developing countries where these diseases are endemic.

Immunoprophylactic effects of the anti-leprosy Mw vaccine in household contacts of leprosy patients: clinical field trials with a follow up of 8-10 years.

We report here a large scale, double blind immunoprophylactic trial of a leprosy vaccine based on Mycobacterium w (Mw) in an endemic area of Kanpur Dehat, Uttar Pradesh, India. A population of 420,823 spread over 272 villages was screened where 1226 multibacillary (MB) and 3757 paucibacillary (PB) cases of leprosy were detected. A total of 29,420 household contacts (HHC) of these patients were screened for evidence of active or inactive leprosy. After exclusion of 1622 contacts for any of the different exclusion criteria, a total of 24,060 HHC could be vaccinated for vaccine or placebo under coding (20,194 administered two doses and 3866 received single dose). The vaccine consisted of 1 x 10(9) heat killed bacilli (Mw) in normal saline for the first dose and half of the first dose, i.e. 5 x 10(8) bacilli for the second dose, given 6 months after the first dose. The placebo consisted of 1/8th dose of the normal dose of tetanous toxoid. Both placebo and vaccine were given under double-blind coding, The contacts were followed up during three surveys at 3, 6 and 9 years after the initial vaccination, for detection of post-vaccination cases (PVCs) and observing any side-effects caused as a result of vaccination. The codes were opened on 24th January 2001, after the analysis of the data following completion of the third and final follow-up survey. When only contacts received the vaccine, Mw vaccine showed a protective efficacy (PE) of 68-6% at the end of first, 59% at the end of the second and 39.3% at the end of the third follow-up survey. When both patients and contacts received the vaccine, the protective efficacy observed was 68%, 60% and 28% at the end of the first, second and third surveys, respectively. When patients, and not the contacts, received the vaccine, a PE of 42.9% in the first, 31% in the second and 3% in the third survey was shown. These results suggest that the vaccination of the contacts is more valuable in achieving the objective of immunoprophylaxis than that of patients, and the vaccine effects are noted maximally in children (as compared to adolescents and adults) who constitute the most responsive group The effect of vaccine is sustained for a period of about 7-8 years, following which there is a need to provide a booster vaccination for the sustained protection.

Neonatal BCG protection against leprosy: a study in Manaus, Brazilian Amazon.

There is clear evidence that BCG protects against leprosy, but cross-immunity with environmental mycobacteria can interfere with vaccination protection. Some have cast doubts whether BCG vaccination can offer a significant impact against leprosy in the Brazilian Amazon, which is an endemic area for leprosy and with a high prevalence of environmental mycobacteria. This study was designed to estimate the vaccine effectiveness of neonatal BCG against leprosy in Amazon region, in Brazil. This is a cohort study nested in a randomized community trial. The study had two main results. First, neonatal BCG vaccination in Brazilian Amazon elicited protection of 74% (95% CI 57-86) against all forms of leprosy cases. Second, the highest protection was observed for multibacillary cases, 93% (95% CI 71-98). It is concluded that the study provides evidence that neonatal BCG may have an important and overlooked impact on the occurrence and transmission of leprosy, maybe even more in the future when the cohort which received a high coverage of BCG reaches the age of high incidence of leprosy.

Under-explored experimental topics related to integral mycobacterial vaccines for leprosy.

Many leprosy vaccine studies have utilized live or killed whole mycobacteria, such as Bacille Calmette-Guérin, Indian Cancer Research Center (ICRC) bacilli and Mycobacterium w either alone or in combination with killed Mycobacterium leprae. For Bacille Calmette-Guérin, the vaccine dose is generally that which gives the largest delayed-type hypersensitivity response with minimal side effects. The doses of other integral mycobacterial vaccines appear to be arbitrarily chosen. Hypotheses governing immunologic responses to complex antigens predict that the doses used may be too high, resulting in protection of some individuals and increasing the susceptibility of other individuals to leprosy. The natural history of an individual's prior exposure to environmental mycobacteria will affect the outcome of protective vaccination using a given dose of mycobacterial vaccine in the individual.

[Eradication of leprosy and public health. Vaccination and multidrug therapy]. / Perspektywy eliminacji tradu w swiecie. Szczepienia ochronne a leczenie etiotropowe.

Leprosy is a disease, which still affects large populations in the developing countries particularly in Africa, Asia and Latin America. For the last 15 years significant advances have been made towards leprosy elimination. The most effective strategy for leprosy control is an early identification of cases and an effective treatment with multidrug therapy (MDT). The vaccination against leprosy plays only an additional role. There are two possible approaches to develop vaccine against leprosy. One is to produce a vaccine based on organisms related to M. leprae, such as: BCG, ICRC bacillus, Mycobacterium w, Mycobacterium vaccae, Mycobacterium habana. However, these organisms related to M. leprae are not very promising in experimental animal studies. In 1970s a new vaccine was prepared based on killed M. leprae. This vaccine, tested alone and together with BCG revealed little impact on increasing vaccine efficacy. The success in cloning and expressing the M. leprae genome in E. coli created the possibility of moving towards a second generation vaccine using peptide antigens. Up till now only MDT has essential impact on decline of global leprosy prevalence. Out of 122 endemic countries in 1985, 107 countries have reached elimination of leprosy at country level. At the end of 2000 leprosy was a public health problem only in 15 countries (prevalence rate > 1/10.000). Currently leprosy remains a problem mainly in 6 major endemic countries. Among these, India alone accounts for 64% of prevalence and 78% of detection worldwide.

Prophylaxis--scope and limitations.

Attempts to prevent leprosy by one or another prophylactic method began with the use of dapsone as a chemoprophylaxis. Following early, small-scale studies, which were promising, large-scale studies with dapsone and acedapsone, both among contacts and in the general population, demonstrated that it is possible to prevent the occurrence of leprosy to a modest extent. With regard to immunoprophylaxis, BCG had long been considered a possibility, particularly in view of its potential to convert the skin test reaction to lepromin. Over the years, major, large-scale field trials of BCG had been carried out in Uganda, Burma, Papua New Guinea and India. All of the studies demonstrated that BCG was capable of preventing leprosy. However, protective efficacy varied from around 20% to greater than 80%. Killed Mycobacterium leprae mixed with BCG has also given varying results. Other vaccines based on cultivable mycobacteria have also been tried, and at least one of them appears promising. An approach to prophylaxis must take into account (a) the level of risk addressed and the perception of risk by the community; (b) the level of efficacy of the method of prophylaxis; (c) the possibility of easily identifying high-risk groups; (d) the operational feasibility; and (e) the focus of the prophylaxis, whether the individual or the community, or both. However, in view of the enormous progress being made towards elimination of leprosy by the widespread application of MDT, prophylaxis is becoming less and less relevant and less and less cost-effective, except in very special situations.

Prospects for low dose BCG vaccination against tuberculosis.

Efficacious vaccination against fast growing pathogens results in a rapid, secondary immune response on natural infection; this provides protection to the vaccinated individual in the race between developing effective immunity and the rapid multiplication of the pathogen. In certain chronic diseases, due to slow growing pathogens, cell-mediated immunity alone can contain the infection, and yet an antibody response is sometimes induced, at the expense of the cell-mediated response, upon natural infection. Such situations arise in leprosy and the leishmaniases and most probably in tuberculosis. AIDS and syphilis. In these cases, the purpose of vaccination must be to ensure that a stable, protective, cell-mediated immune response is inevitably induced upon natural infection. We believe we have developed a general strategy for causing a pathogen-specific imprint upon the immune system so that a stable, protective, cell-mediated response is inevitably induced in all individuals upon natural infection. BALB/c mice are "susceptible" to Leishmania major in the sense that they mount a non-protective antibody response on substantial infection, and consequently suffer chronic and progressive disease. We have demonstrated that infection with low doses of parasites induces only cellular immunity, and establishes the desired imprint. Mice exposed to low doses and challenged some months later with a substantial, normally pathogenic dose of parasites, mount a stable, protective, cell-mediated response and the vaccinated "susceptible" mice withstand the infection. We have recently managed to achieve a similar lock of the immune response of BALB/c mice to BCG into a cell-mediated mode by low-dose exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Protection of mice against mycobacterial infection by lymphoid cell vaccination.

Intracellular parasites may thrive by inducing the host's immune system to suppress the effector immune response that otherwise limits multiplication. Hosts are traditionally immunized with the parasite antigens that induce effector immunity. Alternatively, one might vaccinate the host with the host lymphoid cells involved in suppression. Multiplication of Mycobacterium marinum was prevented by vaccinating mice with cells prepared from the popliteal lymph nodes of mice in which the organisms were multiplying logarithmically, that were inactivated by fixation with glutaraldehyde. Cells obtained later during infection, when the donor mice manifest immunity, did not protect against infection. Thus, it may be possible to influence the course of a microbial infection by immunizing the host not only with components of the organisms, but also with the host components that are exploited by the organism.

Protective efficacy of BCG against leprosy in Northern Malawi.

The effectiveness of a BCG vaccination programme in protecting against leprosy was assessed by case-control and cohort analyses of data from the Lepra Evaluation Project in Karonga District, Northern Malawi. Results indicate that BCG provides at least 50% protection against leprosy in this population and that protection is independent of age, sex, schooling status, or location within the project area. Agreement between these findings and those from a controlled trial in Uganda indicates that BCG is sufficiently effective against leprosy in East and Central Africa to be considered an important element of leprosy control in that region.