Bacille Calmette–Guerin Complications in Newly Described Primary Immunodeficiency Diseases: 2010–2017

Abstract

Bacille Calmette–Guerin (BCG) vaccine is widely used as a prevention strategy against tuberculosis. BCG is a live vaccine, usually given early in life in most countries. While safe to most recipients, it poses a risk to immunocompromised patients. Several primary immunodeficiency diseases (PIDD) have been classically associated with complications related to BCG vaccine. However, a number of new inborn errors of immunity have been described lately in which little is known about adverse reactions following BCG vaccination. The aim of this review is to summarize the existing data on BCG-related complications in patients diagnosed with PIDD described since 2010. When BCG vaccination status or complications were not specifically addressed in those manuscripts, we directly contacted the corresponding authors for further clarification. We also analyzed data on other mycobacterial infections in these patients. Based on our analysis, around 8% of patients with gain-of-function mutations in STAT1 had mycobacterial infections, including localized complications in 3 and disseminated disease in 4 out of 19 BCG-vaccinated patients. Localized BCG reactions were also frequent in activated PI3Kδ syndrome type 1 (3/10) and type 2 (2/18) vaccinated children. Also, of note, no BCG-related complications have been described in either CTLA4 or LRBA protein-deficient patients; and not enough information on BCG-vaccinated NFKB1 or NFKB2-deficient patients was available to drive any conclusions about these diseases. Despite the high prevalence of environmental mycobacterial infections in GATA2-deficient patients, only one case of BCG reaction has been reported in a patient who developed disseminated disease. In conclusion, BCG complications could be expected in some particular, recently described PIDD and it remains a preventable risk factor for pediatric PIDD patients.

BCG Moreau Vaccine Safety Profile and NK Cells—Double Protection Against Disseminated BCG Infection in Retrospective Study of BCG Vaccination in 52 Polish Children with Severe Combined Immunodeficiency

“…However, BCG disseminated infection can rarely occur in TB-NK+ SCID patients with RAG1/2 mutation and patients vaccinated with the BCG Moscow-368 vaccine and the BCG Sofia SL 222 vaccine manufactured in Bulgaria, derived from the Moscow-368 substrain and used in Ukraine since 2014 [51]. The important role of innate immune response to mycobacterial infection has also been demonstrated in a group of newly described PID, particularly those with gain-of-function STAT1 mutation, where decreased STAT1mediated IFN -γ responses impair immunity against mycobacterial infection [34,52].…”

BCG: a vaccine with multiple faces

“…131 As new inborn errors of immunity are described, new forms of BCG susceptibility and complications are recognized, as recently reviewed with the examples of STAT-1 GOF, APDS1 and APDS2 patients. 132 As neonatal BCG is included in the vaccination programs in many countries, it is important to identify and avoid administration of BCG to infants who have immunodeficiencies. To protect these vulnerable patients strategies are to defer the administration of BCG for 2-6 months after delivery or to institute routine newborn screening for severe combined immunodeficiency.…”

Bacillus Calmette–Guerin (BCG) Vaccine-associated Complications in Immunodeficient Patients Following Stem Cell Transplantation

“…Furthermore, neonatal screening does not encompass the wide range of BCG-associated PIDs and is currently not available in the countries with the highest burden of mycobacterial disease. Recommendations to postpone vaccination in at risk infants [ 50 – 52 ] must be weighed against the global health impact of BCG vaccination. Recently, the COVID-19 epidemic has stimulated new interest in the BCG vaccine for its possible non-specific protective effects through trained innate immunity, though evidence of efficacy of BCG vaccination against COVID-19 is lacking [ 53 , 54 ].…”