Differences in responses to the intracellular macrophage environment between Mycobacterium bovis BCG vaccine strains Moreau and Pasteur

BACKGROUND The Bacille Calmette-Guérin (BCG) vaccine comprises a family of strains with variable protective efficacy against pulmonary tuberculosis (TB) and leprosy, partly due to genetic differences between strains. OBJECTIVES Previous data highlighting differences between the genomes and proteomic profiles of BCG strains Moreau and Pasteur led us to evaluate their behaviour in the macrophage microenvironment, capable of stimulating molecular responses that can impact the protective effect of the vaccine. METHODS Strain infectivity, viability, co-localisation with acidified vesicles, macrophage secretion of IL-1 and MCP-1 and lipid droplet biogenesis were evaluated after infection. FINDINGS We found that BCG Moreau is internalised more efficiently, with significantly better intracellular survival up to 96 h p.i., whereas more BCG Pasteur bacilli were found co-localised in acidified vesicles up to 6 h p.i. IL-1β and MCP-1 secretion and lipid droplet biogenesis by infected macrophages were more prominent in response to BCG Pasteur. MAIN CONCLUSION Overall, our results show that, compared to Pasteur, BCG Moreau has increased fitness and better endurance in the harsh intracellular environment, also regulating anti-microbial responses (lower IL-1b and MCP-1). These findings contribute to the understanding of the physiology of BCG Moreau and Pasteur in response to the intraphagosomal environment in a THP-1 macrophage model.

Coronavirus disease 2019 vaccination in patients with psoriasis: A position statement from India by SIG psoriasis (IADVL Academy).

Coronavirus disease 2019 (COVID-19) pandemic has affected every sphere of life including management of psoriasis. The availability of COVID-19 vaccines has given rise to hope and at the same time some apprehensions as well. With the general population becoming eligible for vaccination, there is some confusion, on the eligibility of patients with different medical conditions and patients on immunosuppressive or immunomodulating medications for COVID-19 vaccination. Dermatologists treating psoriasis patients frequently face questions from them, whether they can undergo coronavirus disease 2019 vaccination. A PUBMED search was performed using the following strategy: 'COVID-19' AND 'Vaccine' AND 'Psoriasis'. We also performed a PUBMED search using the following strategy: 'SARS-CoV-2' AND 'Vaccine' AND 'Psoriasis'. All articles irrespective of language and publication date were included to arrive at this position statement. This position statement deals with the safety, eligibility and modifications of treatment, if needed among psoriasis patients with regards to the coronavirus disease 2019 vaccines currently available in India.

Looking back to move forward: A travel rule underlined by the current pandemic.

Learning from the past - is easier said than done. In this narrative, "travel" refers to the forward movement of the society at large on the path of health and development. It is suggested that looking back and learning from the lived experiences of the past outbreaks could help generating public health insights and incorporating them in planning for a better future. In the process, a country may choose to revisit what took place in the recent past during the COVID-19 pandemic within its boundary and beyond. However, unfolding of events in the past, which is not as immediate as COVID neither too far as the flu pandemic of 1918, also has lessons to offer. Recognizably, a few alarms, that rang in the recent past and cried for mass attention towards beefed up public health preparedness, were missed. It is therefore necessary now to critically examine the past-efforts to eradicate, eliminate or control diseases such as small pox, polio, HIV, tuberculosis, leprosy, measles or malaria. Results of such evaluation could inform the future courses of actions around disease elimination science and health (DESH) and help develop better nations.

Tuberculosis vaccine BCG: the magical effect of the old vaccine in the fight against the COVID-19 pandemic.

Bacillus Calmette-Guérin (BCG) is a live attenuated M. bovis vaccine that was developed about 100 years ago by Albert Calmette and Camille Guérin. Many countries have been using the vaccine for decades against tuberculosis (TB). The World Health Organization (WHO) recommends a single dose of BCG for infants in TB endemic as well as leprosy high risk countries, and globally almost 130 million infants are vaccinated yearly. The role of BCG is well known in reducing neonatal and childhood death rates. Epidemiological and retrospective cross-sectional studies demonstrated that the BCG vaccination protects the children against respiratory tract infections and lowers the risk of malaria in children. In addition, BCG enhances IFN-γ and IL-10 levels, thus providing immunity against respiratory tract infection even in elderly people. The BCG is also known to provide nonspecific innate immunity against viruses and parasites, through an innate immune mechanism termed 'trained immunity' and is defined as the immunological recall of the innate immune system by epigenetic reprogramming. Based on these studies it is suggested that the BCG has the potential to act as a protective agent against COVID-19. Further proven safety records of BCG in humans, its adjuvant activity and low-cost manufacturing make it an attractive option to stop the pandemic and reduce the COVID-19 related mortality. In this review we discuss the heterologous effects of BCG, induction of trained immunity and its implication in development of a potential vaccine against COVID-19 pandemic.

Bacillus of Calmette and Guérin (BCG) and the risk of leprosy in Ciudad del Este, Paraguay, 2016-2017.

OBJECTIVES: Paraguay has experienced a 35% reduction in the detected incidence of leprosy during the last ten years, as the vaccination coverage against tuberculosis (Bacillus of Calmette and Guérin [BCG] vaccine) reached ≥95% among infants. The objective of this case-control study was to evaluate the protective effect of BCG on the risk of leprosy. METHODS: We used a population-based case-control study of 20 leprosy confirmed cases reported among residents of Ciudad del Este, Paraguay, diagnosed in 2016-2017. Three controls were selected from a random sample of households from the city. We assessed vaccine effectiveness using 1- odds ratio [OR], and confounding for age, gender, education, occupation, and marital status using stratified and exact logistic regression, and explored if there was effect modification calculating the synergy factor (SF) and relative excess risk due to interaction (RERI). RESULTS: After controlling for age, gender, education, occupation and marital status, the OR of BCG scar on the risk of leprosy was 0.10 (95% confidence interval [CI], 0.02 to 0.45), for an estimate of vaccine effectiveness of 89.5% reduced risk of leprosy (95% CI, 55.2 to 98.1). There was evidence of heterogeneity by which the effectiveness of BCG seemed stronger among younger persons (Breslow-Day and Z-test of the SF had a p<0.05), and both the RERI and SF indicated a less then multiplicative and additive interaction of BCG and younger age. CONCLUSIONS: BCG vaccination was associated with a decreased risk of leprosy in the study population, particularly in persons born after 1980.

Specific Treatment Exists for SARS-CoV-2 ARDS.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), seems to be difficult to overcome. A pandemic of such a scale has not been seen since the 1918 influenza pandemic. Although the predominant clinical presentation is respiratory disease, neurological manifestations and sequelae are increasingly being recognized. We observed a case series of rapid recovery of ARDS within 24 h in the preliminary clinical features of COVID-19 ARDS-associated neurological disease. It was also noted that by 15 April, 2021, there was no SARS-CoV-2 ARDS on Sorok Island in South Korea, where lepers had been living together. We compared each of dapsone's effects on humans and considered those of SARS-CoV-2. Dapsone showed different effects in the brain. The Sorokdo National Hospital reported a relationship between dapsone and the neuroinflammasome of Alzheimer's disease (AD) in Sorok Island from January 2005 to June 2020. AD prevalence was low in the leprosy patient group who took dapsone regularly. The preliminary cross-sectional study of the trial group (22 subjects) and the control group (22 subjects) in the Hunt Regional Hospital reported the following results: The chi-square statistic is 5.1836. The p-value is 0.022801. The result is considered significant at p < 0.05. The results from the medical treatment from 21 December to 29 December 2020 were considered. The mortality rates at the ARDS onset stage were 0% with dapsone administered as a standard COVID-19 treatment and 40% without dapsone administered as a standard COVID-19 treatment, respectively. Based on the respiratory failure and sudden high death rate originating from the involvement of the brainstem, especially the pre-Bötzinger complex, dapsone can be used to significantly reduce the incidence of the cases of acute respiratory distress syndrome and other illnesses caused by SARS-CoV-2.

Antigenic sites in SARS-CoV-2 spike RBD show molecular similarity with pathogenic antigenic determinants and harbors peptides for vaccine development.

The spike protein of coronavirus is key target for drug development and other pharmacological interventions. In current study, we performed an integrative approach to predict antigenic sites in SARS-CoV-2 spike receptor binding domain and found nine potential antigenic sites. The predicted antigenic sites were then assessed for possible molecular similarity with other known antigens in different organisms. Out of nine sites, seven sites showed molecular similarity with 54 antigenic determinants found in twelve pathogenic bacterial species (Mycobacterium tuberculosis, Mycobacterium leprae, Bacillus anthracis, Borrelia burgdorferi, Clostridium perfringens, Clostridium tetani, Helicobacter Pylori, Listeria monocytogenes, Staphylococcus aureus, Streptococcus pyogenes, Vibrio cholera and Yersinia pestis), two malarial parasites (Plasmodium falciparum and Plasmodium knowlesi) and influenza virus A. Most of the bacterial antigens that displayed molecular similarity with antigenic sites in SARS-CoV-2 RBD (receptor binding domain) were toxins and virulent factors. Antigens from Mycobacterium that showed similarity were mainly involved in modulating host cell immune response and ensuring persistence and survival of pathogen in host cells. Presence of a large number of antigenic determinants, similar to those in highly pathogenic microorganisms, not merely accounts for complex etiology of the disease but also provides an explanation for observed pathophysiological complications, such as deregulated immune response, unleashed or dysregulated cytokine secretion (cytokine storm), multiple organ failure etc., that are more evident in aged and immune-compromised patients. Over-representation of antigenic determinants from Plasmodium and Mycobacterium in all antigenic sites suggests that anti-malarial and anti-TB drugs can prove to be clinical beneficial for COVID-19 treatment. Besides this, anti-leprosy, anti-lyme, anti-plague, anti-anthrax drugs/vaccine etc. are also expected to be beneficial in COVID-19 treatment. Moreover, individuals previously immunized/vaccinated or had previous history of malaria, tuberculosis or other disease caused by fifteen microorganisms are expected to display a considerable degree of resistance against SARS-CoV-2 infection. Out of the seven antigenic sites predicted in SARS-CoV-2, a part of two antigenic sites were also predicted as potent T-cell epitopes (KVGGNYNYL444-452 and SVLYNSASF366-374) against MHC class I and three (KRISNCVADYSVLYN356-370, DLCFTNVYADSFVI389-402, and YRVVVLSFELLHA508-520) against MHC class II. All epitopes possessed significantly lower predicted IC50 value which is a prerequisite for a preferred vaccine candidate for COVID-19.

Reverse vaccinology and subtractive genomics approaches for identifying common therapeutics against Mycobacterium leprae and Mycobacterium lepromatosis.

BACKGROUND: Mycobacterium leprae and Mycobacterium lepromatosis are gram-positive bacterial pathogens and the causative agents of leprosy in humans across the world. The elimination of leprosy cannot be achieved by multidrug therapy alone, and highlights the need for new tools and drugs to prevent the emergence of new resistant strains. METHODS: In this study, our contribution includes the prediction of vaccine targets and new putative drugs against leprosy, using reverse vaccinology and subtractive genomics. Six strains of Mycobacterium leprae and Mycobacterium lepromatosis (4 and 2 strains, respectively) were used for comparison taking Mycobacterium leprae strain TN as the reference genome. Briefly, we used a combined reverse vaccinology and subtractive genomics approach. RESULTS: As a result, we identified 12 common putative antigenic proteins as vaccine targets and three common drug targets against Mycobacterium leprae and Mycobacterium lepromatosis. Furthermore, the docking analysis using 28 natural compounds with three drug targets was done. CONCLUSIONS: The bis-naphthoquinone compound Diospyrin (CID 308140) obtained from indigenous plant Diospyros spp. showed the most favored binding affinity against predicted drug targets, which can be a candidate therapeutic target in the future against leprosy.

Insights into Mycobacterium leprae Proteomics and Biomarkers-An Overview.

Although leprosy is curable, the identification of biomarkers for the early diagnosis of leprosy would play a pivotal role in reducing transmission and the overall prevalence of the disease. Leprosy-specific biomarkers for diagnosis, particularly for the paucibacillary disease, are not well defined. Therefore, the identification of new biomarkers for leprosy is one of the prime themes of leprosy research. Studying Mycobacterium leprae, the causative agent of leprosy, at the proteomic level may facilitate the identification, quantification, and characterization of proteins that could be potential diagnostics or targets for drugs and can help in better understanding the pathogenesis. This review aims to shed light on the knowledge gained to understand leprosy or its pathogen employing proteomics and its role in diagnosis.

The role of donor-unrestricted T-cells, innate lymphoid cells, and NK cells in anti-mycobacterial immunity.

Vaccination strategies against mycobacteria, focusing mostly on classical T- and B-cells, have shown limited success, encouraging the addition of alternative targets. Classically restricted T-cells recognize antigens presented via highly polymorphic HLA class Ia and class II molecules, while donor-unrestricted T-cells (DURTs), with few exceptions, recognize ligands via genetically conserved antigen presentation molecules. Consequently, DURTs can respond to the same ligands across diverse human populations. DURTs can be activated either through cognate TCR ligation or via bystander cytokine signaling. TCR-driven antigen-specific activation of DURTs occurs upon antigen presentation via non-polymorphic molecules such as HLA-E, CD1, MR1, and butyrophilin, leading to the activation of HLA-E-restricted T-cells, CD1-restricted T-cells, mucosal-associated invariant T-cells (MAITs), and TCRγδ T-cells, respectively. NK cells and innate lymphoid cells (ILCs), which lack rearranged TCRs, are activated through other receptor-triggering pathways, or can be engaged through bystander cytokines, produced, for example, by activated antigen-specific T-cells or phagocytes. NK cells can also develop trained immune memory and thus could represent cells of interest to mobilize by novel vaccines. In this review, we summarize the latest findings regarding the contributions of DURTs, NK cells, and ILCs in anti-M tuberculosis, M leprae, and non-tuberculous mycobacterial immunity and explore possible ways in which they could be harnessed through vaccines and immunotherapies to improve protection against Mtb.

Spectrum of Inborn errors of immunity in a cohort of 90 patients presenting with complications to BCG vaccination in India.

World Health Organisation recommends the practice of BCG vaccination at birth in countries which have a high incidence of tuberculosis and/or high leprosy burden. The BCG vaccination is considered safe for a competent immune system. However, in children with weakened immune systems cause of which can be primary or secondary, the vaccine may lead to side effects which can be localized or disseminated. In this study, we report a spectrum of inborn errors of immunity (IEI) commonly referred to as primary immunodeficiency disorders (PIDs) diagnosed in a large cohort of patients presenting with complications to BCG vaccination from India. Retrospective data analysis of patients referred to ICMR- National Institute of Immunohematology (ICMR-NIIH) for IEI workup between 2007 and 2019 was done. IEI was identified in n = 52/90 (57.7%) patients presenting with BCG complications. Of these, n = 13(14.4%) patients were diagnosed with severe combined immune deficiency, n = 15(16.7%) with chronic granulomatous disease, n = 19(21.1%) with Inborn errors of IFN-γ immunity, n = 4(4.4%) with Combined immunodeficiency and n = 1(1.1%) with Leucocyte Adhesion Deficiency type1. Majority of cases with BCGosis (88%) had an underlying IEI. This study strongly highlights the need for evaluation of patients with BCG complications for underlying IEI. While disseminated BCGosis strongly predicts underlying IEI, even localized persistent adenitis may be a warning sign of underlying IEI. It is also strongly recommended to record a family history of previous sibling death prior to administration of this live vaccine and deferring live vaccine till the diagnosis of IEI is ruled out in cases with a positive family history.

Reverse vaccinology and subtractive genomics approaches for identifying common therapeutics against Mycobacterium leprae and Mycobacterium lepromatosis

Mycobacterium leprae and Mycobacterium lepromatosis are gram-positive bacterial pathogens and the causative agents of leprosy in humans across the world. The elimination of leprosy cannot be achieved by multidrug therapy alone, and highlights the need for new tools and drugs to prevent the emergence of new resistant strains. Methods In this study, our contribution includes the prediction of vaccine targets and new putative drugs against leprosy, using reverse vaccinology and subtractive genomics. Six strains of Mycobacterium leprae and Mycobacterium lepromatosis (4 and 2 strains, respectively) were used for comparison taking Mycobacterium leprae strain TN as the reference genome. Briefly, we used a combined reverse vaccinology and subtractive genomics approach. Results As a result, we identified 12 common putative antigenic proteins as vaccine targets and three common drug targets against Mycobacterium leprae and Mycobacterium lepromatosis. Furthermore, the docking analysis using 28 natural compounds with three drug targets was done. Conclusions The bis-naphthoquinone compound Diospyrin (CID 308140) obtained from indigenous plant Diospyros spp. showed the most favored binding affinity against predicted drug targets, which can be a candidate therapeutic target in the future against leprosy.(AU)

BCG vaccination: Effects on the patterns of pediatric leprosy.

INTRODUCTION: Leprosy in pediatric population continues to remain as one of the major public health problems in India. BCG vaccination has been implicated in producing some protection against leprosy. OBJECTIVES: The present study intended to find out the patterns of leprosy in the pediatric age group (<12 years) and to determine the proportion of paucibacillary (PB) and multibacillary (MB) leprosy cases among the BCG-vaccinated and nonvaccinated groups. METHODOLOGY: It is a cross-sectional study among patients with leprosy up to the age of 12 years attending a tertiary care hospital in Eastern India by comprehensive history taking and through clinical examination. The history of BCG vaccination was enquired and the BCG scar was looked for to determine the BCG-vaccinated and nonvaccinated group. After collecting the data in a predesigned case sheet, the data were analyzed. RESULT: Of the 137 patients included in this study, 71.53% belonged to the 11-12 years age, 27.74% the 5-10 years age, and 1 patient the <5 year age group. The sex ratio was 1:1.63. PB leprosy was more common than MB leprosy. Smear positivity, deformity, and reaction were not very frequent. Among the vaccinated patients, the ratio of PB and MB leprosy was 5.3:1, while in the nonvaccinated group the ratio was 1.2:1. Data analysis showed that the proportion of MB leprosy was statistically significant in the nonvaccinated group than in the vaccinated group (p = 0.0352). CONCLUSION: Our study pointed that BCG vaccination might have a role in enhancing the cell-mediated immunity (CMI).

The State of Affairs in Post-Exposure Leprosy Prevention: A Descriptive Meta-Analysis on Immuno- and Chemo-Prophylaxis.

OBJECTIVE: Annually, over 200,000 people are diagnosed with leprosy, also called Hansen's disease. This number has been relatively stable over the past years. Progress has been made in the fields of chemoprophylaxis and immunoprophylaxis to prevent leprosy, with a primary focus on close contacts of patients. In this descriptive meta-analysis, we summarize the evidence and identify knowledge gaps regarding post-exposure prophylaxis against leprosy. METHODS: A systematic literature search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was conducted by searching the medical scientific databases Cochrane, Embase, Pubmed/MEDLINE, Research Gate, Scopus and Web of Science on Jan. 22, 2020, using a combination of synonyms for index terms in four languages: "leprosy" and "population" or "contacts" and "prevention" or "prophylaxis." Subsequently, Infolep.org and Google Scholar were searched and the "snowball method" was used to retrieve other potentially relevant literature. The found articles were screened for eligibility using predetermined inclusion and exclusion criteria. RESULTS: After deduplication, 1,515 articles were screened, and 125 articles were included in this descriptive meta-analysis. Immunoprophylaxis by bacillus Calmette-Guérin (BCG) vaccination is known to provide protection against leprosy. The protection it offers is higher in household contacts of leprosy patients compared with the general population and is seen to decline over time. Contact follow-up screening is important in the first period after BCG administration, as a substantial number of new leprosy patients presents three months post-vaccination. Evidence for the benefit of re-vaccination is conflicting. The World Health Organization (WHO) included BCG in its Guidelines for the Diagnosis, Treatment and Prevention of Leprosy by stating that BCG at birth should be maintained in at least all leprosy high-burden regions. Literature shows that several vaccination interventions with other immunoprophylactic agents demonstrate similar or slightly less efficacy in leprosy risk reduction compared with BCG. However, most of these studies do not exclusively focus on post-exposure prophylaxis. Two vaccines are considered future candidates for leprosy prophylaxis: Mycobacterium indicus pranii (MiP) and LepVax. For chemoprophylaxis, trials were performed with dapsone/acedapsone, rifampicin, and ROM, a combination of rifampicin, ofloxacin, and minocycline. Single-dose rifampicin is favored as post-exposure prophylaxis, abbreviated as SDR-PEP. It demonstrated a protective effect of 57% in the first two years after administration to contacts of leprosy patients. It is inexpensive, and adverse events are rare. The risk of SDR-PEP inducing rifampicin resistance is considered negligible, but continuous monitoring in accordance with WHO policies should be encouraged. The integration of contact screening and SDR-PEP administration into different leprosy control programs was found to be feasible and well accepted. Since 2018, SDR-PEP is included in the WHO Guidelines for the Diagnosis, Treatment and Prevention of Leprosy. CONCLUSION: Progress has been made in the areas of chemoprophylaxis and immunoprophylaxis to prevent leprosy in contacts of patients. Investing in vaccine studies, like LepVax and MiP, and increasing harmonization between tuberculosis (TB) and leprosy research groups is important. SDR-PEP is promising as a chemoprophylactic agent, and further implementation should be promoted. More chemoprophylaxis research is needed on: enhanced medication regimens; interventions in varying (epidemiological) settings, including focal mass drug administration (fMDA); specific approaches per contact type; combinations with screening variations and field-friendly rapid tests, if available in the future; community and health staff education; ongoing antibiotic resistance surveillance; and administering chemoprophylaxis with SDR-PEP prior to BCG administration. Additionally, both leprosy prophylactic drug registration nationally and prophylactic drug availability globally at low or no cost are important for the implementation and further upscaling of preventive measures against leprosy, such as SDR-PEP and new vaccines.

Bacillus Calmette-Guérin (BCG) vaccine generates immunoregulatory cells in the cervical lymph nodes in guinea pigs injected intra dermally.

This work demonstrates the presence of immune regulatory cells in the cervical lymph nodes draining Bacillus Calmette-Guérin (BCG) vaccinated site on the dorsum of the ear in guinea pigs. It is shown that whole cervical lymph node cells did not proliferate in vitro in the presence of soluble mycobacterial antigens (PPD or leprosin) despite being responsive to whole mycobacteria. Besides, T cells from these lymph nodes separated as a non-adherent fraction on a nylon wool column, proliferated to PPD in the presence of autologous antigen presenting cells. Interestingly, addition of as low as 20% nylon wool adherent cells to these, sharply decreased the proliferation by 83%. Looking into what cells in the adherent fraction suppressed the proliferation, it was found that neither the T cell nor the macrophage enriched cell fractions of this population individually showed suppressive effect, indicating that their co-presence was necessary for the suppression. Since BCG induced granulomas resolve much faster than granulomas induced by other mycobacteria such as Mycobacterium leprae the present experimental findings add to the existing evidence that intradermal BCG vaccination influences subsequent immune responses in the host and may further stress upon its beneficial role seen in Covid-19 patients.

Mycobacterium leprae: Pathogenesis, diagnosis, and treatment options.

Mycobacterium leprae is known to cause leprosy, a neurological and dermatological disease. In the past 20 years, 16 million leprosy cases have been recorded and more than 200,000 new cases were registered each year, indicating that the disease is still progressing without hindrance. M. leprae, an intracellular bacterium, infects the Schwann cells of the peripheral nervous system. Several types of leprosy have been described, including indeterminate, tuberculoid, borderline tuberculoid, mid-borderline, borderline lepromatous and lepromatous, and three different forms of leprosy reactions, namely type 1, 2 and 3, have been designated. Microscopic detection, serological diagnostic test, polymerase chain reaction and flow tests are employed in the diagnosis of leprosy. The recommended treatment for leprosy consists of rifampicin, dapsone, clofazimine, ofloxacin and minocycline and vaccines are also available. However, relapse may occur after treatment has been halted and hence patients must be educated on the signs of relapse to allow proper treatment and reduce severity. In this review, we depict the current understanding of M. leprae pathogenicity, clinical aspects and manifestations. Transmission of leprosy, diagnosis and treatment are also discussed.

Environmental modifiers of RTS,S/AS01 malaria vaccine efficacy in Lilongwe, Malawi.

BACKGROUND: RTS,S/AS01 is the first vaccine against malaria to undergo pilot implementation, beginning in 2019 and vaccinating 360,000 children per year in Malawi, Ghana, and Kenya. The four-dose vaccine is given as a primary three-dose series with a fourth dose given approximately 18 months later. The efficacy of RTS,S/AS01 was variable among the 11 sites participating in the 2009-2014 phase III trial (MALARIA-055, NCT00866619), possibly due to differences in transmission intensity. However, a within-site examination of environmental factors related to transmission intensity and their impact on vaccine efficacy has yet to be conducted. METHODS: We implemented the phase III RTS,S/AS01 trial at the Malawi site, which enrolled 1578 infants (6-12 weeks) and children (5-17 months) living in the Lilongwe District in Central Malawi and followed them for 3 years between 2009 and 2014. A global positioning system survey and an ecological questionnaire were conducted to collect participant household locations and characteristics, while additional data on background malaria prevalence were obtained from a concurrent Malaria Transmission Intensity (MTI) survey. Negative binomial regression models were used to assess whether the efficacy of the vaccine varied by estimated background malaria prevalence, household roof type, or amount of nearby vegetation. RESULTS: Vaccine efficacy did not significantly vary by estimated malaria prevalence or by roof type. However, increased vegetation cover was associated with an increase in the efficacy of the three-dose primary RTS,S/AS01 series in the 18 months before the fourth dose and a decrease in the efficacy of the primary vaccine series in the second 18 months following, if the fourth dose was not given. Vegetation cover did not alter the efficacy of the fourth dose in a statistically or practically significant manner. CONCLUSIONS: Vegetation coverage in this study site might be a proxy for nearness to rivers or branching, shallow wetlands called "dambos" which could serve as breeding sites for mosquitoes. We observed statistically significant modification of the efficacy of RTS,S/AS01 by forest cover, suggesting that initial vaccine efficacy and the importance of the fourth dose varies based on ecological context. TRIAL REGISTRATION: Efficacy of GSK Biologicals' Candidate Malaria Vaccine (257049) Against Malaria Disease Caused by P. falciparum Infection in Infants and Children in Africa. NCT00866619 prospectively registered 20 March 2009.

The immunology of other mycobacteria: M. ulcerans, M. leprae.

Mycobacterial pathogens can be categorized into three broad groups: Mycobacterium tuberculosis complex causing tuberculosis, M. leprae and M. lepromatosis causing leprosy, and atypical mycobacteria, or non-tuberculous mycobacteria (NTM), responsible for a wide range of diseases. Among the NTMs, M. ulcerans is responsible for the neglected tropical skin disease Buruli ulcer (BU). Most pathogenic mycobacteria, including M. leprae, evade effector mechanisms of the humoral immune system by hiding and replicating inside host cells and are furthermore excellent modulators of host immune responses. In contrast, M. ulcerans replicates predominantly extracellularly, sheltered from host immune responses through the cytotoxic and immunosuppressive effects of mycolactone, a macrolide produced by the bacteria. In the year 2018, 208,613 new cases of leprosy and 2713 new cases of BU were reported to WHO, figures which are notoriously skewed by vast underreporting of these diseases.

Proposing BCG Vaccination for Mycobacterium avium ss. paratuberculosis (MAP) Associated Autoimmune Diseases.

Bacille Calmette-Guerin (BCG) vaccination is widely practiced around the world to protect against the mycobacterial infection tuberculosis. BCG is also effective against the pathogenic mycobacteria that cause leprosy and Buruli's ulcer. BCG is part of the standard of care for bladder cancer where, when given as an intravesicular irrigant, BCG acts as an immunomodulating agent and lessens the risk of recurrence. Mycobacterium avium ss. paratuberculosis (MAP) causes a fatal enteritis of ruminant animals and is the putative cause of Crohn's disease of humans. MAP has been associated with an increasingly long list of inflammatory/autoimmune diseases: Crohn's, sarcoidosis, Blau syndrome, Hashimoto's thyroiditis, autoimmune diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis, lupus and Parkinson's disease. Epidemiologic evidence points to BCG providing a "heterologous" protective effect on assorted autoimmune diseases; studies using BCG vaccination for T1D and MS have shown benefit in these diseases. This article proposes that the positive response to BCG in T1D and MS is due to a mitigating action of BCG upon MAP. Other autoimmune diseases, having a concomitant genetic risk for mycobacterial infection as well as cross-reacting antibodies against mycobacterial heat shock protein 65 (HSP65), could reasonably be considered to respond to BCG vaccination. The rare autoimmune disease, relapsing polychondritis, is one such disease and is offered as an example. Recent studies suggesting a protective role for BCG in Alzheimer's disease are also explored. BCG-induced energy shift from oxidative phosphorylation to aerobic glycolysis provides the immunomodulating boost to the immune response and also mitigates mycobacterial infection-this cellular mechanism unifies the impact of BCG on the disparate diseases of this article.