{
  "abstract": "Abstract Objective To evaluate the safety and efficacy of VPM1002 and Immuvac in reducing the incidence of microbiologically confirmed tuberculosis (TB; pulmonary TB and extrapulmonary TB), development of latent TB infection, and immunogenicity.Design Phase 3 randomised clinical trial (PreVenTB trial).Setting 18 sites across six states of India.Participants 12 717 healthy household contacts (aged ≥6 years) of patients with a smear positive TB test.Interventions Participants were randomly assigned in a 1:1:1 ratio (using block randomisation with variable sample size) to receive an intradermal injection of VPM1002, Immuvac, or placebo in both arms. After one month, a second dose was administered in one arm to 11 829 healthy participants.Outcome measures The primary outcome was efficacy against confirmed TB (pulmonary TB and extrapulmonary TB) over 38 months of follow-up. Secondary outcomes were development of latent TB infection, adverse and serious adverse events, efficacy in predefined age groups, and immunogenicity. Exploratory outcomes were efficacy when considering tuberculin skin test status, and post hoc analyses of efficacy in participants aged 6-14 and according to body mass index.Results 252 and 227 participants developed microbiologically confirmed TB in modified intention-to-treat and per protocol groups, respectively. The per protocol analysis showed 65 (1.68%), 80 (2.09%), and 82 (2.13%) participants developed TB in the VPM1002, Immuvac, and placebo groups, respectively. Of these, 12 (0.31%), 16 (0.42%), and 24 (0.62%) developed extrapulmonary TB in the VPM1002, Immuvac, and placebo groups, respectively. In the per protocol analysis, VPM1002 showed vaccine efficacy of 21.4% (95% confidence interval (CI) −8.9% to 43.2%), 19.5% (−14.6% to 43.4%), and 50.4% (0.8% to 75.2%) against all TB, pulmonary TB, and extrapulmonary TB, respectively. Immuvac showed vaccine efficacy of 33.2% (−25.9% to 64.5%) against extrapulmonary TB. VPM1002 and Immuvac showed vaccine efficacy of 64.9% (−2% to 90.1%) and 66.3% (1.9% to 90.5%) against extrapulmonary TB in participants with tuberculin skin test positivity. Both vaccines were well tolerated with mild local reactions in about a third of participants. VPM1002 and Immuvac induced Mycobacterium tuberculosis specific polyfunctional CD4+ T cells. Post hoc analyses showed vaccine efficacy of 64.6% (95% CI 16.3% to 85.1%) against all forms of TB, 62.1% (3.0% to 85.2%) against pulmonary TB, and 77.6% (−3.7% to 95.2%) against extrapulmonary TB in participants aged 6-14 years in the VPM1002 group.Conclusions Both vaccines were safe but did not show any efficacy against all forms of microbiologically confirmed TB or pulmonary TB. VPM1002 showed considerable efficacy against extrapulmonary TB. Both vaccines showed efficacy against extrapulmonary TB in participants who had a positive tuberculin skin test.Trial registration Clinical Trials Registry India CTRI/2019/01/017026.",
  "authors": [
    {
      "affiliations": [
        "Indian Council of Medical Research, Delhi, India"
      ],
      "name": "Manjula Singh"
    },
    {
      "affiliations": [
        "Bhagwan Mahavir Medical Research Centre (BMMRC), Hyderabad, India"
      ],
      "name": "Sindhu Joshi"
    },
    {
      "affiliations": [
        "National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India"
      ],
      "name": "Vikram Vohra"
    },
    {
      "affiliations": [
        "National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India"
      ],
      "name": "Rohit Sarin"
    },
    {
      "affiliations": [
        "National Institute of Translational Virology & AIDS Research (Formerly National AIDS Research Institute, Pune), Pune, India"
      ],
      "name": "Suchit Vasant Kamble"
    },
    {
      "affiliations": [
        "National Institute for Research in Tuberculosis, Chennai, India"
      ],
      "name": "Banurekha Velayutham"
    },
    {
      "affiliations": [
        "All India Institute of Medical Sciences, New Delhi, India"
      ],
      "name": "Anant Mohan"
    },
    {
      "affiliations": [
        "All India Institute of Medical Sciences, New Delhi, India"
      ],
      "name": "Urvashi B Singh"
    },
    {
      "affiliations": [
        "All India Institute of Medical Sciences, New Delhi, India"
      ],
      "name": "Rakesh Kumar"
    },
    {
      "affiliations": [
        "Indian Council of Medical Research, Delhi, India",
        "Regional Medical Research Center, Bhubaneshwar, India"
      ],
      "name": "Sanghamitra Pati"
    },
    {
      "affiliations": [
        "S C B Medical College and Hospital, Cuttack, India"
      ],
      "name": "Manoranjan Pattnaik"
    },
    {
      "affiliations": [
        "All India Institute of Medical Sciences, Bhubaneshwar, India"
      ],
      "name": "Prasanta Raghab Mohapatra"
    },
    {
      "affiliations": [
        "National Tuberculosis Institute, Bengaluru, India"
      ],
      "name": "Uma Shankar"
    },
    {
      "affiliations": [
        "National Tuberculosis Institute, Bengaluru, India"
      ],
      "name": "Somashekar Narasimhaiah"
    },
    {
      "affiliations": [
        "Vardhman Mahavir Medical College and Safdarjung Hospital, Delhi, India"
      ],
      "name": "Geeta Yadav"
    },
    {
      "affiliations": [
        "National Institute for Research in Tuberculosis, Chennai, India"
      ],
      "name": "Syed Hissar"
    },
    {
      "affiliations": [
        "St John’s Medical College, Bengaluru, India"
      ],
      "name": "Rashmi Rodrigues"
    },
    {
      "affiliations": [
        "National Institute of Translational Virology & AIDS Research (Formerly National AIDS Research Institute, Pune), Pune, India"
      ],
      "name": "Abhijit Vasantrao Kadam"
    },
    {
      "affiliations": [
        "National Institute for Research in Tuberculosis, Chennai, India"
      ],
      "name": "Paul Kumaran Paramasivam"
    },
    {
      "affiliations": [
        "SHARE INDIA Mediciti Institute of Medical Sciences (MIMS), Medchal, Malkagiri, India"
      ],
      "name": "Sailaja Kambhampati"
    },
    {
      "affiliations": [
        "National Institute for Research in Tuberculosis, Chennai, India"
      ],
      "name": "Ariarathinam Newtonraj"
    },
    {
      "affiliations": [
        "National Institute for Research in Tuberculosis, Chennai, India"
      ],
      "name": "Natarajan Alangudi Palaniappan"
    },
    {
      "affiliations": [
        "National Institute for Research in Tuberculosis, Chennai, India"
      ],
      "name": "S Devarajulu Reddy"
    },
    {
      "affiliations": [
        "All India Institute of Medical Sciences, Bhubaneshwar, India"
      ],
      "name": "Sourin Bhuniya"
    },
    {
      "affiliations": [
        "Regional Medical Research Center, Bhubaneshwar, India"
      ],
      "name": "Bijaya Kumar Mishra"
    },
    {
      "affiliations": [
        "National Institute of Translational Virology & AIDS Research (Formerly National AIDS Research Institute, Pune), Pune, India"
      ],
      "name": "Ashwini Shete"
    },
    {
      "affiliations": [
        "National Institute for Research in Tuberculosis, Chennai, India"
      ],
      "name": "Luke Elizabeth Hanna"
    },
    {
      "affiliations": [
        "All India Institute of Medical Sciences, New Delhi, India"
      ],
      "name": "Dipendra Kumar Mitra"
    },
    {
      "affiliations": [
        "Indian Council of Medical Research, Delhi, India",
        "National Institute of Translational Virology & AIDS Research (Formerly National AIDS Research Institute, Pune), Pune, India"
      ],
      "name": "Samiran Panda"
    },
    {
      "affiliations": [
        "All India Institute of Medical Sciences, New Delhi, India"
      ],
      "name": "Randeep Guleria"
    },
    {
      "affiliations": [
        "National Institute for Research in Tuberculosis, Chennai, India"
      ],
      "name": "Srikanth Tripathy"
    },
    {
      "affiliations": [
        "Vardhman Mahavir Medical College and Safdarjung Hospital, Delhi, India"
      ],
      "name": "Neelam Roy"
    },
    {
      "affiliations": [
        "St John’s Medical College, Bengaluru, India"
      ],
      "name": "George D’Souza"
    },
    {
      "affiliations": [
        "National Tuberculosis Institute, Bengaluru, India"
      ],
      "name": "S K Tripathy"
    },
    {
      "affiliations": [
        "Indian Council of Medical Research, Delhi, India"
      ],
      "name": "Kiran Katoch"
    },
    {
      "affiliations": [
        "Indian Council of Medical Research, Delhi, India"
      ],
      "name": "Ravindra M Pandey"
    },
    {
      "affiliations": [
        "Indian Council of Medical Research, Delhi, India"
      ],
      "name": "Seema Sah"
    },
    {
      "affiliations": [
        "Indian Council of Medical Research, Delhi, India"
      ],
      "name": "Manisha Kashyap"
    },
    {
      "affiliations": [
        "Indian Council of Medical Research, Delhi, India"
      ],
      "name": "Vinay Telasey"
    },
    {
      "affiliations": [
        "Indian Council of Medical Research, Delhi, India"
      ],
      "name": "Meenakshi Bakshi"
    },
    {
      "affiliations": [
        "Clinical Development Services Agency (CDSA), THSTI, Faridabad, India"
      ],
      "name": "Nitya Wadhwa"
    },
    {
      "affiliations": [
        "Indian Council of Medical Research, Delhi, India"
      ],
      "name": "Abdul Mabood Khan"
    },
    {
      "affiliations": [
        "Indian Council of Medical Research, Delhi, India"
      ],
      "name": "Raman R Gangakhedkar"
    },
    {
      "affiliations": [
        "Indian Council of Medical Research, Delhi, India"
      ],
      "name": "Rajni Rani"
    }
  ],
  "title": "Efficacy and safety of VPM1002 and Immuvac in preventing tuberculosis: phase 3 randomised clinical trial (PreVenTB trial)",
  "uid": "e5f32951-44c6-53ab-b864-f1a3228cfc3e"
}