BCG Vaccine in Reducing Morbidity and Mortality in Elderly Individuals in COVID-19 Hotspots
Condition: COVID
Study type: Interventional
Phase: Phase 3

Summary: 
      Rationale: SARS-CoV2 viral infection is spreading rapidly throughout the world and in India
      the epidemic poses a major threat to the public health system. Elderly individuals,
      especially those with diabetes, hypertension, other chronic diseases are at high risk of
      mortality. Strategies to protect these individuals are desperately needed to safeguard
      continuous patient care. Bacille Calmette-Guérin (BCG) is a vaccine against tuberculosis,
      with protective non-specific effects against other respiratory tract infections in in-vitro
      and in-vivo studies, and reported significant reductions in morbidity and mortality. Based on
      the capacity of BCG to reduce the incidence of respiratory tract infections in children and
      adults, to exert antiviral effects in experimental models; and to reduce viremia in an
      experimental human model of viral infection, the hypothesis is that BCG vaccination will
      partially protect against mortality in high-risk, elderly individuals.

      Primary Objective: To evaluate the effectiveness of BCG vaccination in preventing morbidity
      and mortality due to COVID-19 in elderly individuals aged between 60 to 80 years living in
      COVID-19 hotspots in India.

      Secondary objectives:

        1. To evaluate the effectiveness of BCG vaccination in terms of

             1. reducing the cumulative incidence of hospital admission and Intensive Care
                admission

             2. reducing the incidence of other respiratory febrile illness

        2. To determine the innate and adaptive immune responses, IgM, IgG and IgA antibody titers
           generated by BCG vaccination (both total and SARS-Cov2 specific) in a subset of
           individuals.

        3. To measure biomarkers induced by BCG vaccination as correlates of risk/protection
           against SARS-Cov2 in a subset of individuals

      Method and Analysis:

      Study design: Intervention study Study population: Elderly 60 - 80 years of age residing in
      designated hotspots for SARS-Cov2 infection Study Intervention: One dose of 0.1ml BCG
      vaccine, given intradermally. Elderly individuals not vaccinated from the same hotspot area
      or from neighbouring hotspot wards areas will be considered as the controls. Study sites:
      Chennai, Mumbai, Ahmedabad, Bhopal, Jodhpur and New Delhi. Study Sample size: 1450
      individuals between 60-80 years of age will receive BCG vaccination while 725 individuals
      will be controls without vaccination Study duration: 6 months/participant. Enrolment at each
      site will be over: 4 months. Each participant will be followed for 6 months post vaccination.
      Primary Outcome Measures: During the study period (6-months), Proportion of individuals
      receiving the BCG vaccination who are asymptomatic but become PCR-positive or seroconvert
      during the 6-month of study period. Proportion of patients with development of COVID-19
      disease (either PCR-positive or seroconvert with symptoms) during the study period.
      Proportion of patients with Severe COVID-19 disease and death due to Covid-19 disease
    

Detailed description: 
      Recruitment area: Under the Lockdown 2.0, the country has been classified into three key
      zones-Red, Orange and Green (26). These zones will support the cluster containment plan
      announced by the government, while opening up the rest of the places.

      Green Zone: Places which have so far not reported even a single COVID-19 positive case will
      be declared as Green Zone under Government's new plan. This means nearly 400+ districts of
      India might qualify to be tagged as Green Zone.

      Orange Zone: Orange zone may see opening of limited public transport and also allow
      exemptions for essential services personnel and farming and harvest activity for the ongoing
      season. Orange zone will have less than 15 cases of COVID-19.

      Red Zone: A district or cluster declared as a red zone, will see severe restrictions with
      zero or no activity allowed. Typical understanding is that any place with more than 15
      COVID-19 positive cases can be declared as a red zone. Investigators will include the Red &
      Orange zones of Delhi, Madhya Pradesh, Maharashtra, Gujarat, Tamilnadu, Rajasthan and other
      interested states for this study.

      Recruitment methods: Participants would be recruited through (i) information presented in
      community organizations, hospitals, colleges and other institutions to the general public.
      (ii) From a line list prepared of adults above the age of 60 years from Census data for the
      hotspot areas. (iii) Participants will also be recruited by use of an advertisement +/-
      registration form formally approved by the ethics committee(s) and distributed or posted in
      the

        1. newspapers or other literature for circulation.

        2. Via presentations (e.g. presentations at lectures or invited seminars). (iv) Community
           Advisory Board will be created for this study and help of the members of this board will
           be taken for recruitment to the study Interested individuals will be provided detailed
           information about the study and the requirements for participation will be provided.
           Participants will be given brochure about the study and patient information sheet. They
           will have the opportunity to ask any questions they might have and to talk to a study
           team member. If they are still interested and willing to participate, they will be
           invited to participate in screening evaluation procedure.

      Study Procedures: Participants meeting inclusion criteria will be recruited in a
      nonrandomized manner after obtaining their consent to participate to the study. An
      information document that clearly indicates the risks and the benefits associated with the
      participation to the study will be given to each patient before signing consent. Regarding
      participant identification, a study number will be assigned sequentially to included
      participants, according to the range of patient numbers allocated to each study center.

      Participants will be seen at baseline for enrolment, initial data collection (a detailed
      medical history including h/o previous BCG vaccination and evidence of BCG vaccination scar
      to be noted), Chest x-ray PA view to rule out PTB, blood sampling for antibody testing (2 ml)
      and PCR (nasopharyngeal swab).

      Eligible participants will be administered BCG at day 0. Participants will be followed up
      weekly by phone for first 2 months and asked to complete a standardized questionnaire. Month
      1, 3 & 6 will be visit in person while Month 2 & 5 will be completed over phone. Participants
      would be tested for COVID antibodies at month 3 and month 6. If positive, nasal/throat swab
      would be collected for PCR testing for confirmation. Participants will also be asked to call
      the study staff in the event of any adverse reactions or illness. Participants will
      thereafter be followed up monthly for six months.

      Participants will be given a diary card (paper), with instructions to fill in case of adverse
      events, along with the emergency 24 hour telephone number to contact the on-call study
      physician if needed. They will be instructed on how to self-assess the severity of these AEs.
      There will also be space on the diary card to self-document unsolicited AEs, and whether
      medication was taken to relieve the symptoms.

      In addition to blood, nasopharyngeal swabs will be collected from all participants.

      qRT- PCR test will be considered to reconfirm the qRT-PCR positive / negative status at
      enrolment. In a subset of this cohort (15% of the sample), consenting for immunological
      substudy, 20 ml of blood will be collected at baseline for immunological and biomarker
      analysis. They will also provide additional blood samples (20 ml) at 1, 3 and 6 months post
      vaccination for immunological and biomarker studies.

      Blood collection: Investigators will collect 2 ml of venous blood after obtaining consent
      from participants. Investigators will collect the specimen using a syringe following all the
      safety precautions and transfer the specimen to serum separator tubes. After completion of
      sample collection from all eligible participants, the specimen will be transported to the
      nearest District Public Health Laboratory (DPHL)/Virus Research and Diagnostic Laboratory
      Network (VRDLN) laboratory in cold chain. In the laboratory, serum will be separated and used
      for rapid antibody testing. Detection of SARS-CoV 2 specific antibodies will be performed
      using a ICMR validated SARS-CoV-2 Antibody Test. The Lateral Flow-based
      immune-chromatographic test detects SARS-CoV 2 specific antibodies (IgG/IgM) with a
      turnaround time of 15-20 mins. Presence of coloured bands at Test and Control lines will
      indicate the presence of SARS-CoV-2 antibodies (positive result) in the specimen. Absence of
      coloured band in Test line will indicate the absence of SARS-CoV-2 antibodies (negative
      result).

      Immunology analysis: The primary variables of interest of immune response to vaccines will be
      the percentage of CD4+ and CD8+ T cells that express IFN-γ, TNF, IL-2, IL-17, IL-22, CD107a,
      Perforin, Granzyme B and Granulysin alone or in combination in response to stimulation with
      SARS-Cov-2 and BCG antigens. Secondary variables of interest would be the response of trained
      monocytes and other innate immune cells including NK cells, NKT cells, gd T cells and MAIT
      cells. Response will be measured by flow cytometry in the intracellular cytokine staining
      (ICS) assay. Blood collected for immunological studies will be utilized as follows: PBMC
      isolation and storage for immunology studies described above; Whole blood in Lithium Heparin
      microtainer for absolute blood cell counting by flow cytometry (deconvolution for
      transcriptomics) and for Interferon Gamma Release Assays; plasma and serum for soluble immune
      mediators by ELISA and for total and SARS-Cov2 specific IgG, IgM and IgA ELISA.

      Diagnostic tests:

      PCR: Molecular diagnosis of SARS-Cov2 will be done by using RT-PCR kits according the ICMR
      guidelines. Serology: Antibody IgG/IgM Covid-19 rapid test kit will be used. Chest x-ray
      along with symptom screening: To rule out tuberculosis

      Subgroup Analysis

        1. The primary analysis will be performed using the whole cohort

        2. A stratified analysis will be undertaken for various age groups and by risk groups based
           on co-morbidity. This will allow vaccine effectiveness to be assess in more homogeneous
           subgroups and to check for effect of modification across strata

        3. Stratified analysis will also be done for various geographic distribution and occupation

        4. Immunological analysis will be carried out in a subset of individuals (n=200)
    

Intervention name(s): BCG vaccine (Freeze-dried)
Intervention type(s): Biological
Intervention description(s): single dose of BCG vaccine (Freeze-dried) manufactured by Serum Institute of India, Pune. The composition of BCG vaccine is Live, attenuated BCG (Bacillus Calmette-Guerin Strain). (Each 1 ml contains between 2 x 106 and 8 x 106 Colony Forming Units (C.F.U.) with Diluent: Sodium Chloride Injection I.P.)
Intervention MeSH terms: BCG Vaccine
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Intervention model description: In this study, as we are employing a control group that is not vaccinated against the disease to be prevented, but some clinical data are available to support the likely efficacy of the candidate vaccine, we will use unbalanced randomization and enrol participants to control group in the ratio of 2:1, so that majority of the study participant will receive the vaccine
Masking: None (Open Label)
Primary purpose: Prevention