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

Introduction

Current Clinical Trial Updates• The bacillus Calmette-Guérin (BCG) vaccine, originally introduced
a century ago for tuberculosis prevention, has been shown inepidemiological studies and randomized clinical trials to protect
humans from diverse infectious diseases

Adult Trials• In an 8-year, Phase I randomized clinical trial in adults withlongstanding T1D (no pancreas C-peptide), BCG vaccinations
induced long-term improvements in glycemic control• In an open-label trial, subjects with T1D, but not latent autoimmune
diabetes of adults (LADA), responded to BCG vaccinations with
HbA1c lowering within two years (Fig. 1)• In a randomized, double-blinded, placebo-controlled Phase II/IIItrial, BCG had 92% efficacy vs placebo against COVID-19 (Table 2)• Recent randomized Phase I-III human clinical trials suggest BCGmay 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 thewhite blood cells (WBC) of subjects with T1D• BCG-treated lymphocytes become a major consumer and regulator ofblood sugars in vivo
• WBC with accelerated glycolysis stop sugar transport when bloodsugar is < 50 mg/dl• BCG restores the underlying sugar transport defects in the WBCs ofthose 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)/Harvard
Medical School testing BCG’s ability to lower HbA1c, reduce
insulin requirements and regulate blood sugars in T1D; studies arealso looking at BCG’s ability to protect from infectious disease

Figure 1. Open-label trial: In vivo BCG
vaccinations decrease HbA1c in T1D, not LADAA.

In an open-label clinical trial in adults withlongstanding T1D (n=62), the HbA1c response insubjects with T1D with juvenile onset (age of onset[AOO] ≤21), LADA (AOO >21), and untreatedcontrols were evaluated.
(A.) Juvenile-onset T1D subjects (n=6; mean
AOO=11±3 y) (left) were compared with LADA
subjects (n=10; mean AOO=31±2 y) (right) for
responsiveness (% change from baseline 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 asignificant trend (repeated-measures ANOVAp=0.01; left). The trend in LADA was not significant(repeated-measures ANOVA p=0.58; right). Meancurrent chronological age of the study groups: 28±3y (T1D) and 45±4 y (LADA). Mean duration ofdiabetes: 18±3 y (T1D) and 19±2 y (LADA).

B.

(B.) HbA1c percent change from baseline in T1D
subjects with juvenile onset receiving Tokyo BCG
treatment is shown in red (n=6) and compared withpreviously published Phase I clinical trial data using
Sanofi BCG in patients with similarly early onset(11±5.8 y) (black, open triangle). Also shown are
the Phase I placebo group (open squares) and areference population (closed squares).

• Here we present an update on the BCG studies at MGH

Table 1. T1D Patient Enrollment & Follow-Up
Timelines for BCG Studies

Phase I +CrossoverRadiology
Study
Phase II
Study
Transition
Study
Phase II
Crossover
COVID-BCG
Study
Phase II
Pediatric
Study
Total:

BCGTotal #TreatedSubjects(n)52
9Control/Placebo(n)43660150

10050292906NANA

143*

9548250125125636364266

Trial TypeTime Followed/DurationRandomized,
Double-Blind
Open-Label

5 or 10 y/10 y

Randomized,
Double-Blind
Open-Label~4 y/5 yRandomized,
Double-BlindRandomized,
Double-BlindRandomized,
Double-Blind~3 y/5 y

1.5 y/5 y
2 y/5 y33 mo/33 mo
1 y/5 y• To date, all T1D subjects in randomized trials have long-term
diabetes except for the subgroup of new-onset subjects enrolled in
the pediatric study• Current ongoing 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 BCGtreatment; 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 in subjects with ≥ 2 years T1D and with new-onset T1D*The COVID-BCG study uses the randomized Phase II subjects for infectious
disease monitoring.

Table 2. U.S. COVID-BCG study: BCG primary
vaccinations provide protection from COVID-19
Posteriorprobability(Vaccineefficacy > 30%)

BCG
(n=96)

Placebo Surveillance Vaccine(n=48)
durationefficacy(months)(Confirmed by pointof care + SARs
CoV-2 antibodies)1(1.0%)

6(12.5%)

1592%

0.99

COVID-19 cases0(0.0%)

5(10.4%)15100%

0.99

COVID-19 cases(Confirmed by PCR)

Pediatric Trial• A Phase II double-blind, placebo-controlled, randomized trial has
enrolled 90/150 planned long-term subjects (ages 11 to <18 y; ≥ 2 yof T1D; 45 have received BCG) and enrollment 100 of new-onset
subjects is underway (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 to stop pancreas-driven
disease; will also evaluate pancreas preservation in those withsignificant C-peptide

Conclusions• In longstanding T1D, the primary mechanism for BCG vaccine
efficacy is correction of underlying aerobic glycolysis defects inWBCs, restoring regulated glucose transport for lowered andimproved HbA1c values; BCG also gradually induces Tregs• The impact of multi-dose BCG vaccination in MS and T1D takes
approximately 2 years to manifest, but effects appear durable
without further treatment to > 8 years• BCG vaccine therapy may offer a safe, affordable intervention inlongstanding autoimmunity; new pediatric clinical trials will study theimpact of BCG-induced Tregs on pancreas preservation
Refs: 1. Kühtreiber WM, NPJ Vaccines (2018); 2. Shpilsky GF, iScience (2021); 3. Dias HF, Vaccine (2022).
www.postersession.com
Funding Acknowledgement: The Iacocca Foundation. No conflicts of interest to declare. Contact: dfaustman@mgh.harvard.edu