BCG Clinical Trial Programs in Advanced Type 1 Diabetes: 2023 Update
WM Kühtreiber, G Wolfe, M Vaishnaw, J Braley, H Zheng, & DL Faustman
MASSACHUSETTS GENERAL HOSPITAL & HARVARD MEDICAL SCHOOL, BOSTON, MA, USA

Introduction• The bacillus Calmette-Guérin (BCG) vaccine,originally introduced a century ago for tuberculosis
prevention, has been shown in epidemiologicalstudies and randomized clinical trials to protect
humans from diverse infectious diseases• Recent randomized Phase I-III human clinical
trials suggest BCG may also protect humans from
immune diseases such as type 1 diabetes (T1D)
and multiple sclerosis (MS)• Immune and metabolic mechanisms account for
BCG’s durable ability to regulate glucose control
in T1D1-3:– BCG corrects underlying aerobic glycolysis
defects in white blood cells (WBCs) of subjects
with T1D•••

BCG-treated lymphocytes become a major
consumer & regulator of blood sugars in vivo
WBCs with accelerated glycolysis stop sugartransport when blood sugar is < 50 mg/dl
BCG restores the underlying sugar transport
defects in the WBCs of those with T1D to levels
closer to normal– Gradually (over 3 years) BCG induces potent
regulatory T cells (Tregs) to suppress
autoimmunity• Multiple randomized human clinical protocols(Table 1) are underway at Massachusetts General
Hospital (MGH) testing BCG’s ability to lower
HbA1c, reduce insulin requirements and regulate
blood sugars in T1D; studies are also looking at
BCG’s ability to protect from infectious disease• Here we present an update on the BCG studies atMGH

Table 1. T1D patient enrollment &follow-up timelines for MGHBCG studies
BCGTotal #TreatedSubjects(n)Phase I +CrossoverRadiology
Study
Phase II
Study
Transition
Study
Phase II
Crossover
COVID-BCG
Study
Phase II
Pediatric Study
Total:

Control/Placebo(n)52943660150

100

50292906NANA

143*

95

48250

125125636

364

266

Trial
TypeTime
Followed/
Duration

Randomized, 5 or 10 y/10 y
Double-Blind
Open-Label~3 y/5 y
Randomized,
Double-Blind
Open-LabelRandomized,
Double-BlindRandomized,
Double-BlindRandomized,
Double-Blind~4 y/5 y
1.5 y/5 y
2 y/5 yAdult Trial Updates• In an 8-year, Phase I randomized clinical trial in adults
with longstanding T1D (no pancreas C-peptide), BCG
induced long-term improvements in glycemic control• In an open-label trial, subjects with T1D, but not latent
autoimmune diabetes of adults (LADA), had HbA1clowering within two years of BCG vaccinations (Fig. 1)• In a randomized, double-blinded, placebo-controlled
Phase II/III trial, BCG had 92% efficacy vs placebo
against COVID-19 (Table 2)Open-label: In vivo BCG vaccinations
decrease HbA1c in T1D, not LADA

Table 2. U.S. COVID-BCG study: BCG
primary vaccinations provide
protection from COVID-19BCG(n=96)

Placebo(n=48)

COVID-19 cases(Confirmed bypoint of care +SARs CoV-2antibodies)1(1.0%)

COVID-19 cases(PCR confirmed)

0(0.0%)A.

•

Current studies use multi-dose BCG; Tokyo 174 strain•

Study groups include: 1) 10-year follow up of a Phase
I adult study to evaluate the durability of lowered
HbA1c values after BCG treatment; 2) Randomized,
double-blind Phase II adult clinical trial to demonstrate
the reproducibility of Phase I findings; 3) Radiologic
study to quantify and identify organs/organ systems
with higher sugar utilization after BCG treatment; 4)
Adult study comparing 2 vs 6 doses of BCG over 5
years of observation; 5) Pediatric trial of BCG insubjects with ≥ 2 years T1D and with new-onset T1D*COVID-BCG study uses the randomized Phase II subjects for infectious
disease monitoring.

6(12.5%)

1592%

0.99

5(10.4%)15100%

0.99• Phase II double-blind, placebo-controlled, randomized
trial: 90/150 planned long-term subjects are enrolled(ages 11 to <18 y; ≥ 2 y of T1D; 70 have receivedBCG); enrollment of 100 new-onset subjects isunderway (ages 8 to <18 y; ≥ 3 mo to < 1 y of T1D)
• Trial will evaluate BCG’s ability to restore aerobic
glycolysis, improve blood sugars and induce Tregs tostop pancreas-driven disease; will also study pancreas
preservation in those with significant C-peptide

1 y/5 yTo date, all T1D subjects in randomized trials havelong-term diabetes except for the subgroup of newonset subjects enrolled in the pediatric study

Vaccineefficacy

Pediatric Trial Updates

33 mo/33 mo•

Posteriorprobability(Efficacy>30%)

Surveillance
duration(months)

B.

Conclusions•Fig. 1. In an open-label clinical trial in adults with longstanding T1D (n=62), HbA1c response wasevaluated in subjects with: T1D with juvenile onset (age of onset [AOO] ≤21), LADA (AOO >21), anduntreated T1D controls. (A.) Juvenile-onset T1D subjects (n=6; mean AOO=11±3 y) (left) werecompared with LADA subjects (n=10; mean AOO=31±2 y) (right) for responsiveness (% change frombaseline HbA1c) to BCG Tokyo strain vaccines over a 2-year period and to a T1D reference
population not receiving BCG. The fall in HbA1c in juvenile-onset T1D is a significant trend (repeatedmeasures ANOVA p=0.01; left). The trend in LADA was not significant (repeated-measures ANOVA
p=0.58; right). Mean current chronological age of study groups: 28±3 y (T1D) and 45±4 y (LADA).
Mean duration of diabetes: 18±3 y (T1D) and 19±2 y (LADA). (B.) HbA1c percent change frombaseline in T1D subjects with juvenile onset receiving Tokyo BCG treatment is shown in red (n=6) andcompared with previously published Phase I clinical trial data using Sanofi BCG in patients withsimilarly early onset (11±5.8 y) (black, open triangle). Also shown are the Phase I placebo group(open squares) and a reference population (closed squares).

••In longstanding T1D, BCG vaccine therapy corrects
underlying aerobic glycolysis defects in WBCs,
restoring regulated glucose transport for lowered,improved HbA1c values; also gradually induces Tregs
Multi-dose BCG vaccination impact in MS and T1Dtakes ~2 years to manifest, but effects appear durable
without further treatment to >8 years
BCG vaccine therapy may offer a safe, affordable
intervention in longstanding autoimmunity

Refs: 1. Kühtreiber WM, NPJ Vaccines (2018); 2. Shpilsky GF, iScience (2021); 3. Dias HF, Vaccine (2022). Funding Acknowledgement: Iacocca Foundation. No conflicts of interest to declare.
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Contact: dfaustman@mgh.harvard.edu
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