Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly
Authors: Maria Tsilika
Simone Moorlag
Dionyssia-Irene Droggiti
Athanassios Karageorgos
Georgia Damoraki
Mihai G Netea
Evangelos J Giamarellos-Bourboulis
Evdoxia Kyriazopoulou
Antigone Kotsaki
Jorge Domínguez-Andrés
Amalia Bolanou
Theologia Gkavogianni
Hans Koenen
Antonios Papadopoulos
Reinout van Crevel
Nikolaos Antonakos
Maria-Evangelia Adami
Panagiotis Koufargyris
George Renieris
Journal: Cell (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: BCG; cytokines; elderly; epigenetic modifications; infection incidence
Affiliations: 4(th) Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, 124 62 Athens, Greece. Electronic address: ., 4(th) Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, 124 62 Athens, Greece., Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6500 Nijmegen, the Netherlands., Department of Laboratory Medicine, Radboud University Medical Center, 6500 Nijmegen, the Netherlands., Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6500 Nijmegen, the Netherlands; Department of Immunology and Metabolism, Life & Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.

Abstract:  BCG vaccination in children protects against heterologous infections and improves survival independently of tuberculosis prevention. The phase III ACTIVATE trial assessed whether BCG has similar effects in the elderly. In this double-blind, randomized trial, elderly patients (n = 198) received BCG or placebo vaccine at hospital discharge and were followed for 12 months for new infections. At interim analysis, BCG vaccination significantly increased the time to first infection (median 16 weeks compared to 11 weeks after placebo). The incidence of new infections was 42.3% (95% CIs 31.9%-53.4%) after placebo vaccination and 25.0% (95% CIs 16.4%-36.1%) after BCG vaccination; most of the protection was against respiratory tract infections of probable viral origin (hazard ratio 0.21, p = 0.013). No difference in the frequency of adverse effects was found. Data show that BCG vaccination is safe and can protect the elderly against infections. Larger studies are needed to assess protection against respiratory infections, including COVID-19 (ClinicalTrials.gov NCT03296423). 

Retracted: No

PubPeer comments:
 Can authors please explain what was used as a placebo? I am skeptical about the double-blind design of the study. BCG vaccine is the ONLY known intra-dermal vaccination, which results in a strong local inflammation and typically leaves an apparent scar. These  side effects of BCG vaccination is almost universally observed. What were the ingredients of placebo vaccines used in this study? Did they also trigger a similar local inflammation and a scar? If not, how could this be properly double-blinded, as both physicians (researchers) and research subjects knew what they had? If this could be an concern, I would be skeptical about potential biases from the flawed research design. , 
 Well, OK. I just dug a bit more into the NCT clinical trial website: https: clinicaltrials.gov ct2 show NCT03296423 Placebo Comparator: Placebo One intradermal injection of 0.1ml of sodium chloride 0.9% was used as a placebo. Again, I am surprised by this double-blind experiment design. How can this be properly double-blinded as both some of the researchers and probably most participants know whether they had BCG or placebo? As the differences presented in this paper are mostly statistically significant, but subtle. The considerations of placebo effect, Hawthorne effect, and observer bias need to be better controlled. ,