Clinical and Immune Impact of Mycobacterium bovis BCG Vaccination Scarring

Abstract

The World Health Organization recommends Mycobacterium bovis BCG vaccination in areas of high tuberculosis prevalence. BCG's clinical and immune effects, not necessarily Mycobacterium tuberculosis specific, are unclear. BCG vaccine scarring often is used as a surrogate marker of vaccination or of effective vaccination. We evaluated BCG scarring status in relation to clinical findings and outcome in 700 hospitalized Malawians, of whom 32 had M. tuberculosis bloodstream infections (BSI) (10 of whom had cellular immune studies done) and of whom 48 were infants <6 months old and therefore recently vaccinated (19 of whom had immune studies). In the patients >6 months old, scarring was not related to the presence of pulmonary symptoms (35 versus 30%), chronic cough or fever, mortality, or M. tuberculosis BSI. In M. tuberculosis BSI patients, scarring was unrelated to mortality, vital signs, or clinical symptoms but those with scarring had higher proportions of memory and activated T cells and more type 2-skewed cytokine profiles. Infants with either BCG scarring (n ‫؍‬ 10) or BCG lesional inflammation (n ‫؍‬ 5) had no symptoms of sepsis, but 18 of 33 infants without BCG vaccination lesions did. Those with BCG lesions had localized infections more often than did those without BCG lesions. These infants also had lower median percentages of lymphocytes spontaneously making interleukin-4 (IL-4) or tumor necrosis factor alpha (TNF-␣) and lower ratios of T cells spontaneously making IL-4 to T cells making IL-6. Thus, we found that, in older patients, BCG vaccine scarring was not associated with M. tuberculosis-specific or nonspecific clinical protection. Those with M. tuberculosis BSI and scarring had immune findings suggesting previous M. tuberculosis antigen exposure and induction of a type 2 cytokine pattern with acute reexposure. It is unlikely that this type 2 pattern would be protective against mycobacteria, which require a type 1 response for effective containment. In infants <6 months old, recent BCG vaccination was associated with a non-M. tuberculosis-specific, anti-inflammatory cytokine profile. That the vaccinated infants had a greater frequency of localized infections and lesser frequency of sepsis symptoms suggests that this postvaccination cytokine pattern may provide some non-M. tuberculosis-specific clinical benefits.

BCG stimulated dendritic cells induce an interleukin‐10 producing T‐cell population with no T helper 1 or T helper 2 bias in vitro

“…25,26 However, there is an increasing number of studies indicating that BCG might also induce immune-regulatory responses. A recent study has revealed higher IL-10 production in systemic T cells and monocytes of BCG-vaccinated children, 14 which suggest activation of the anti-inflammatory immune axis. Furthermore, a study of TB patients and healthy BCG-vaccinated subjects has shown elevated pro-as well as anti-inflammatory cytokines by PBMCs in response to MTB antigens, represented by higher levels of IFN-c, TNF-a and IL-10 in both groups.…”

“…Interestingly, the infants with a BCG scar had higher anti-inflammatory responses, represented by higher ratios of interleukin-10 (IL-10)-producing to IL-4-producing T cells, as well as higher ratios of IL-10-producing to IL-6-producing monocytes in their blood. 14 These results might suggest that BCG vaccination early in life leads to a more robust regulatory network, which prevents excessive inflammatory responses associated with overt pathology, organ failure and death.…”

Landscape Analysis of Interactions between Nutrition and Vaccine Responses in Children

“…The serum retinol concentration was measured at the time of follow-up and children were classified as VA severely deficient (serum retinol ,0.35 mmol/L), VA deficient (serum retinol ,0.70 mmol/L), or normal (serum retinol $0.70 mmol/L) (79). The authors reported that significantly more children with VA deficiency had a visible scar generated by BCG than children with normal VA status.…”

A Heterologous DNA Priming- Mycobacterium bovis BCG Boosting Immunization Strategy Using Mycobacterial Hsp70, Hsp65, and Apa Antigens Improves Protection against Tuberculosis in Mice

“…TB is the greatest cause of death due to a single pathogen, and it is a leading killer among people infected with human immunodeficiency virus or AIDS. Mycobacterium bovis bacillus Calmette Guérin (BCG) is the only vaccine available for clinical use and protects children against miliary tuberculosis (13); however, it has shown variable levels of efficacy against pulmonary TB, as demonstrated by several clinical trials (7). For example, a major trial in The United Kingdom showed Ͼ75% protection (9); however, trials in south India and Malawi demonstrated that BCG fails to consistently protect against pulmonary TB (7,19).…”