Tuberculosis (TB) is still considered a major threat to public health around the world. According to WHO 2020 Global TB report, annually 10 million new TB cases are reported, of which an estimated 1.5 million die due to the disease.1 2 India accounts for 27%, that is, more than a quarter of the global TB burden.1 These alarming figures call for an urgent need to adopt aggressive strategies for prevention and control of TB. India is committed to develop novel strategies to defeat the disease and envisions elimination of TB by the year 2025. An effective vaccine might prove to be a key tool in this endeavour.3
Rationale for the trial
The TB infection is almost exclusively transmitted from active, sputum positive, pulmonary TB (PTB) patient through aerosol route, with the highest risk of transmission to the healthy household contacts (HHCs).4 5 HHCs at younger age and/or with immunodeficiency have a higher risk of TB acquisition.6 7 WHO guidelines for prevention of TB in HHCs of PTB patients recommend combinations of isoniazid with rifapentine or rifampicin for shorter period like 3 months and individually rifampicin or isoniazid for 4 and 6 months respectively.2 However, drug-associated toxicity warrants a need for a preventive TB vaccine that will be immunoprophylatic. There are at least 14 potential vaccine candidates reported for TB prevention with promising results.2 8
Currently, BCG, the only available vaccine, is effective in preventing TB in children but not in adults.9 10 However, a recombinant BCG vaccine VPM1002, expressing listeriolysin (LLO, encoded by the gene hly) of Listeria monocytogenes and deficient in urease C gene (ureC) (BCG _ureC::hly, VPM1002), seems to be promising.11 The mechanism of action of VPM1002 to combat M.Tb has been described in several publications.11–13 VPM1002 has been developed by Vakzine Projekt Management in Germany and licensed to the Serum Institute of India. Preclinical and clinical data indicate that VPM1002 is immunogenic and may be better than available vaccines in terms of safety. Based on encouraging results of two phase I clinical trials in healthy adults, two phase II clinical trials in newborn babies and a clinical trial for prevention of TB recurrence in cured PTB patients,11–13 we selected VPM1002 for phase III trial in India.
Another highly promising candidate vaccine for TB is Immuvac, earlier known as Mycobacterium w (Mw) and later renamed as MIP (Mycobacterium indicus pranii). Immuvac is a heat killed suspension of MIP, a non-pathogenic, cultivable atypical mycobacterium,14 which shares cross-reactive antigens with M. leprae and M. Tb. MIP has been shown to provide significant protection against TB in both BCG responder and non-responder strains of mice.15–17 It has been found to be safe with immunoprophylactic effect in a population-based double-blind placebo-controlled trials against both TB and leprosy.14 18MIP is approved and is marketed by Cadila Pharma for treatment of leprosy as an adjunct therapy along with multidrug therapy under its commercial name Immuvac. In another landmark study, MIP has shown promise as an adjunct to DOTS in treatment of category II PTB.19 MIP is an immunomodulatory vaccine that reduced bacterial load, improved pathology and organised granulomatous response postinfection in the MIP-immunised Guinea pigs.20 MIP induced an increase in protective Th1 immune response initially, followed by decrease in the inflammatory response and increase in the immunosuppressive response, resulting in improvement of lung pathology in Guinea pigs.20 21
Based on several studies on safety, efficacy and immunomodulatory effects of MIP and VPM1002, we planned to conduct a phase III trial for prevention of TB in HHCs of patients with TB. The present study is designed to evaluate the efficacy, safety and tolerability of both VPM1002 and Immuvac (MIP) vaccines among HHCs, of TB patients who are ≥6 years of age, in a double-blind, randomised placebo-controlled phase III clinical trial.
The primary objective of this trial is to evaluate the efficacy of VPM1002 and Immuvac in reducing the incidence of TB among the HHCs of newly diagnosed sputum positive PTB patients from different parts of India, over 3 years’ observational period, after vaccination.
Secondary Objectives of the study are as follows:
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To evaluate the efficacy of VPM1002 and Immuvac in prevention of latent TB infection (LTBI).
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To evaluate the safety of VPM1002 and Immuvac in HHCs.
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To evaluate efficacy of vaccine in prevention of PTB/extra PTB (PTB/EPTB) in different age groups (6–18 years, 19–35 years, 36–60 years and above 60 years).
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To evaluate the Immunogenicity of VPM1002 and Immuvac as compared with placebo against TB.
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