Covid-19 related delays in project launch

The purpose of this study is to assess the efficacy of Bacille Calmette-Guérin (BCG) vaccination compared to placebo against acute respiratory infections in the elderly who are less protected by standard vaccines against influenza than other age groups. The investigators hypothesize that BCG vaccination can reduce incidence of infection and severity of a range of acute respiratory infections. Patients who are residents of participating long-term care facilities (LTCFs), who agree to participate in the study, or with a legal guardian who agrees on their behalf, will be randomly assigned to receive BCG vaccination or a placebo. Participants will be followed for up to six months to assess the incidence of infection and the severity of a range of acute respiratory infections.

This is a Phase III, double-blind, randomized placebo-controlled trial comparing efficacy of BCG vaccination to that of placebo in reducing severity of a range of acute respiratory infections. Participants will need to meet eligibility criteria in order to be included in the study. Those selected will be asked to provide a blood sample for complete blood count, liver function and renal tests, tests to calculate MELD score, also serological testing.

Participants will be randomized in a 1:1 allocation to receive intradermal administration of BCG vaccination or placebo at baseline. During follow-up, the study team will monitor participants' health status by using intermittent surveys about the presence of adverse events potentially related to vaccination, clinic visits or hospitalization for acute respiratory infection, BioFire® Respiratory 2.1 panel for respiratory pathogens and disease outcome status.

The investigators will screen 980 individuals to enroll 830 participants, resulting in 415 receiving BCG vaccine and 415 receiving placebo. The proposed enrollment sample size is designed to provide 80% power to detect 60% vaccine efficacy (a relative risk of 0.4 among the vaccinated) with 0.05 type-1 error in a two-tailed test, assuming 10% lost to follow-up. The number of individuals screened assumes about 15% will not be eligible to be enrolled after screening.

Objective: To measure the impact of one-time BCG-Japan vaccination on acute respiratory infections leading to hospitalization in the elderly.

Primary Endpoint 1: The cumulative incidence of hospitalization for acute respiratory infection following BCG vaccination compared to that following placebo, starting from 14 days post-vaccination, as defined using relevant ICD-10 codes.

If BCG vaccine is shown to be effective in this age group, it will be of major benefit to both study participants and other elderly individuals at risk for acute respiratory infections and have added protection from disease. Identification of an intervention that can reduce the risk of infection and/or of being hospitalized with ARI would reduce the number of new cases and reducing the number of cases that require hospital admission and vast resources.

Inclusion Criteria:

• Clients of a long-term care facility
• 55-85 years old

Exclusion Criteria:

• Known previous or current active TB disease

• Exposure to individual with documented active TB within previous three months

• Fever (>37.5 C) within the past 24 hours

• Current serious underlying medical conditions:

  • HIV+
  • Currently taking immunosuppressive or immunomodulatory drugs
  • Expect to receive chemotherapy or radiation therapy in the coming six months, receipt of chemotherapy in the past six months or undergoing chemotherapy
  • Currently on any anti-cytokine therapy
  • History of organ or bone marrow transplantation
  • Individual or family history of familial or acquired immune disorder, including auto-immune disorders
  • Neutropenia/leukopenia (<500 neutrophils/mm3 or <400 lymphocytes/mm3)
  • Chronic kidney disease (Glomerular Filtration Rate< 30 ml/min/1.73m2)
  • Elevated liver enzymes (alanine aminotransferase >260 IU/L or aspartate aminotransferase >200 IU/L) or Model for End-Stage Liver Disease (MELD) score ≥30
  • Treatment with oral or intravenous steroids at the time of screening, defined as daily doses of 10mg prednisone or equivalent for longer than 3 months.
  • Solid or hematologic malignancy including lymphoma, leukemia and other reticuloendothelial system carcinomas within the past two years.
  • Presence of Parkinson's disease
  • Evidence of dermatitis at site of vaccination

• Living with someone with HIV, immunocompromised, taking immunosuppressive drugs

• Suspicion of active viral or bacterial infection, or taking antivirals or antibiotics

• Any vaccine administration two weeks before or after BCG administration. For those who have received the Covid-19 vaccine, the two weeks are considered after the 2nd dose.

  • Doctors in Taiwan do not always encourage the use of Covid-19 vaccination due to low incidence of disease and the risk of death due to blood clots in the only approved vaccine for use (AstraZeneca).

• Known allergy to components of the BCG vaccine or prior serious reaction to previous BCG administration

• Plan to leave the long-term care facility within the next three months

• Taking part in any ongoing trial that includes administration of an investigational product relevant to respiratory disease

• Participants with cognitive impairment whose legal guardians cannot be contacted

Participants and investigators will be blinded. Designated staff whose responsibility will be to administer the BCG vaccine or placebo will not be blinded. These designated staff members will not be involved in the collection of outcome data