The Value of BCG and TNF in Autoimmunity

Denise Faustman

• Publisher: Academic Press
• Year: 2018
• ISBN:
  9780081025901
• Edition: 2
• Topic: Medicina
• Subtopic: Inmunología

The Value of BCG and TNF in Autoimmune Diseases, Second Edition provides an overview on the current research related to TNF induction and the use of the BCG vaccine as a potential treatment approach to diverse forms of autoimmunity, allergies, infections and neurologic diseases. Since the initial conference (2013) and first edition of this book (2014), the field of BCG research has grown considerably. This new edition contains updates on MS and diabetes, and features at least eight additional chapters on new prevention and treatment trials in autoimmunity and allergy, along with a new understanding of the genetics of BCGs.

• Brings a different perspective on treatment approaches for certain autoimmune conditions
• Gives insight into the how the BCG vaccine impacts gene expression and the durability of the BCG vaccines in long lasting clinic effects
• Discusses TNF induction, rather than anti-TNF, as a therapeutic pathway for autoimmunity treatment
• Covers new topics, such as the Epigenetics of tuberculosis, BCG in neurological disease, BCG in early childhood and allergy, BCG in large prevention trials, Gene expression of BCG and re-methylation of genes, and more

Chapter 1

BCG: Its Impact on Tuberculosis and Relevance to Autoimmune Disease

Barry R. Bloom Harvard T.H. Chan School of Public Health, Boston, MA, United States

Abstract

Bacille Calmette-Guerin (BCG) remains the most widely used vaccine in the world, given to infants and children to protect against tuberculosis (TB). Although all BCG has been derived from the same Pasteur strain a century ago, BCG vaccine strains genetically vary, although all BCG strains have lost a critical cluster of virulence genes found in M. tuberculosis and M. bovis. The variation in protective efficacy of BCG vaccines varies from 87% to 0% in different trials around the world, which remains a puzzle; the best explanation is prior exposure of populations to various environmental mycobacteria. BCG vaccines are also reported to nonspecifically protect against a number of diseases, including diabetes, superficial bladder cancer, multiple sclerosis, and all-cause mortality of children in developing countries. Possible mechanisms underlying protection in these conditions are discussed in this chapter.

Keywords

Vaccine; Tuberculosis; Diabetes; Th cells; CTL; Treg; Macrophages; Antibodies; Cytokines; Cathelicidin

Contents

• Origins
• Current BCG Vaccines
• BCG and Protection Against TB
• Mechanism of Protection
• Nonspecific Effects of BCG
• Some Intriguing Connections With Diabetes
• References

Origins

For centuries, TB was the largest cause of death in the world. Regrettably, TB currently remains the largest cause of death from any infectious disease, with about 10.5 million new cases and 1.5 million deaths each year.¹ The pathogens causing human TB are Mycobacterium tuberculosis (Mtb), transmitted by aerosol, and Mycobacterium bovis, transmitted by milk, which are even more virulent in humans. In 1908, Calmette and his associate, Guerin, working at the Institute Pasteur in Lille, sought to attenuate a virulent M. bovis strain by using the serial culture method devised by Pasteur, that we now know allows random mutations to accumulate. After 39 passages, they noticed a morphology change in some colonies, and after 230 passages, this strain (BCG), which had shown little toxicity and significant protection against TB in a variety of experimental animal models including nonhuman primates, was given for the first time in 1921 to a child at high risk for TB whose mother died of the disease and whose grandmother had active TB. That child survived to old age. Initially and for many years, BCG was given orally, but BCG is currently given intradermally. BCG remains the most widely utilized vaccine in the world, given to more than 100 million children a year and received by more than 4 billion to date worldwide. In animal models, CD4 and CD8 T cells appear to be necessary for protection, as are cytokines including IFN-γ and TNF-α, but the immunologic mechanisms underlying protection in humans remain unknown.

Current BCG Vaccines

All BCG strains originated from the original Pasteur strain, but in the absence of modern methods for freezing, they were passaged under different conditions in many other laboratories (Fig. 1.1). BCG, like Mtb and M. bovis, grows slowly with a doubling time of about 24 h. Currently, the most widely used strains are Pasteur 1173P2, Danish SSI, Glaxo 1077, Tokyo 172-1, Russian BCG-I, Moreau RDJ, Montreal strain, and Tice strain, which is the only one licensed for use in the United States. With the exception of the Glaxo strain grown in liquid culture, the other strains are grown as pellicles on medium and harvested. The semidry mass is then broken up in a ball; milled into single bacilli, small clumps, and fragments; and are then lyophilized. One mg represents about 10⁸ colony-forming units, and the portion of viable bacilli in most preparations ranges between 5% and 45%.^2–4

Fig. 1.1 Genealogy of BCG vaccine strains based on historical data.⁴

BCG and Protection Against TB

Attenuating Mutations in BCG. The genomic DNA sequences of Mtb, M. bovis, and BCG are 99% homologous and colinear, indicating strong evolutionary similarities.⁵ There are many polymorphisms and a number of large deletions, known as Regions of Difference (RD) that distinguish their sequences and virulence. The critical attenuating mutation is a deletion in RD1 that controls a set of secreted products of the Esx loci, which are essential for virulence and absent in all BCG strains. Two secreted proteins of the Esx-1 locus are major antigens of Mtb recognized by T cells and antibodies, and represent the basis of Elispot tests that can distinguish infection by Mtb from tuberculin skin test (TST)-positive conversions caused by BCG.⁶ Three BCG strains (BCG Japan, BCG Glaxo, and BCG Moreau) have lost the ability to produce important lipid virulence factors, and those strains appear to have fewer adverse effects in clinical studies.⁷ BCG vaccines are given intradermally generally close to the time of birth.

Protective Efficacy Against TB. Many randomized control trials, case-control trials, and observational studies have been carried out testing the protective efficacy of BCG vaccines against TB, and the results have varied enormously between trials in different countries. A recent systematic analysis of all randomized control trials has been carried out (Fig. 1.2).⁸ The variation in protection ranged between 88% in the British Medical Research Council (MRC) trial to 0% in the Chingleput trial in South India. The most striking aspect of the variability is the geographic variance in protection; at higher latitudes, BCG had greater efficacy than in developing countries closer to the equator. In all Western European countries and the United States, the incidence of TB has been declining for a century, and it has been difficult to establish the impact of BCG in that context. For example, the Netherlands and the United States—which never employed BCG on a large scale but instead focused on screening for TST positivity and isoniazid preventive therapy, in contrast to the United Kingdom and Scandinavia, which instituted national BCG vaccine programs—had similar declines in incidence. BCG vaccine was more effective when given to young school children or infants. Although variation in many biological characteristics are found between different vaccine strains, for example in an ability to induce TST reactivity, the strain differences did not seem to be a major determinant of variation, and TST has not been a useful predictor of protective efficacy.

Fig. 1.2 Types of protection against Mycobacterium tuberculosis (TB) in children vaccinated with BCG. (Modified from Roy A, Eisenhut M, Harris RJ, et al. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. BMJ. 2014;349(August 5):g4643. https://doi.org/10.1136/bmj.g4643.)

Variability. Multiple hypothesis have been put forward to explain the wide variation between different trials, for example, the lack of critical protective antigens in Mtb, loss of potency by years of passage of strains, and different genetics of human populations. But the different effectiveness in latitudes is a clue to what is generally accepted to be the most likely explanation, namely interference by atypical or nontuberculous mycobacteria (NTM) in the environment. There are more than 300 species of NTM, and in animal studies, a gradient of protective efficacy is seen against Mtb challenge with M. microti and M. kansasii being as effective as BCG, and others engendering little or no protection. In the South India trial, when testing for skin test reactivity to tuberculins derived from an M. avian strain, it was found that, by the age of 9, two-thirds of the children were positive, and 97% were positive by age 15. Hence prior exposure to cross-reactive antigens has an impact on the efficacy of BCG. It is unclear whether the failure to detect protection in individuals with prior exposure is due to protection already engendered by the environmental mycobacteria, such that the additional immunologic impact of BCG is reduced or negligible, or due to a blocking of the development of protective immunity by the NTM.

It is unclear how long protection induced by BCG persists. There is case-report evidence of children developing disseminated BCGosis a dozen years after immunization, so some organisms may persist in some individuals for long periods of time, but most evidence suggest that protective immunity wanes over the first decade or two after vaccinat...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Contributors
• Introduction
• Chapter 1: BCG: Its Impact on Tuberculosis and Relevance to Autoimmune Disease
• Chapter 2: The Potential of TNF Induction From BCG for the Treatment of Type 1 Diabetes
• Chapter 3: Bacille Calmette-Guérin (BCG) Vaccine in Neuroinflammation
• Chapter 4: Host Epigenetic Modifications in Mycobacterium tuberculosis Infection: A Boon or Bane
• Chapter 5: Mycobacterium Bovis Bacille Calmette-Guerin Vaccination: Can Biomarkers Predict Efficacy?
• Chapter 6: The Heterologous Effects of Bacillus Calmette-Guérin (BCG) Vaccine and Trained Innate Immunity
• Chapter 7: Nonspecific Effects of Neonatal Bacille Calmette-Guérin (BCG) Vaccination—From West African Observations to a Danish Randomized Clinical Trial
• Chapter 8: Epigenetic Rewiring of Monocytes in BCG Vaccination
• Chapter 9: Mycobacteria, Immunoregulation, and Autoimmunity
• Chapter 10: mTORC1 Links Cellular Metabolism and Immune Functions in Mycobacterium tuberculosis Infection and BCG Vaccination
• Chapter 11: The Role of Maternal Priming and Boosting for the Nonspecific Effects of BCG Vaccine
• Index