Serum Institute of India Pvt. Ltd. - the world's largest manufacturer of vaccines by numbers of doses - alongside its European partners propose to leverage Bacille Calmette-Guérin (BCG) vaccine's beneficial heterologous ("off-target") effects and proven antiviral and immune modulatory properties that protect against infectious diseases other than tuberculosis. Thus, we plan to conduct a multicentre, randomized, double-blinded, placebo-controlled trial to demonstrate the efficacy of VPM1002 (a recombinant BCG) in mitigating the clinical course of COVID-19 among (1) high-risk persons of advanced age; and (2) high-exposure healthcare professional (HCP).
BCG is an attenuated live vaccine introduced into clinical practice in the 1920s. It is the most widely used vaccine worldwide and has a strong safety profile. BCG-induced innate immune training reduces experimental human viremia with RNA viruses, and in animal models reduces virus-associated death. Randomized trials in older adults and observational studies in children show that BCG markedly reduces acute respiratory infection. BCG is well known as a profound stimulator of innate immune responses. It induces genome-wide epigenetic reprogramming of innate immune cells leading to long-term functional changes and modulation of immunity. The World Health Organisation (WHO) has called for randomized trials to evaluate BCG's off-target effects. VPM1002 is an improved recombinant BCG with the M. bovisurease C gene replaced by the listeriolysin O-encoding gene hly. This further enhances innate immunity and induces strong T cell responses. Compared with other types of BCG, VPM1002 has more potent heterologous effects which could be demonstrated in clinical trials in the context of bladder cancer immunotherapy. Extensive safety data in adults and children have been published. Most importantly and unlike other BCGs, VPM1002 is produced with more uniform inter-batch reliability using methods that allow rapid scalability to billions of doses required to meet immediate global need. Taken together, characteristics of VPM1002 that include 1) safety, 2) more potent protective heterologous effects and 3) scalability, poses VPM1002 to be a promising intervention against SARS-CoV-2.
The COVID-19 pandemic is rapidly worsening in all parts of the world, overwhelming health systems with demand for care that exceeds deliverable capacity and is compounded by high disease rates among healthcare staff. Notwithstanding their unprecedented rapid development, SARS-CoV-2 vaccines are many months away from widespread mass deployability. VPM1002 may act to ameliorate disease severity and mitigate transmission. Even moderate individual efficacy can have dramatic impact at population level through direct (reducing severe disease burden on health systems) and likely through indirect (transmission reduction) influence on pandemic progression. Hence, it can contribute to sustained health systems during this rapidly increasing crisis by offering a safe, affordable and available vaccine. Investment in large scale manufacturing will depend on strong evidence of efficacy from randomized evaluation and would be a worthwhile global effort even if superseded in 1 to 2 years by a specific SARS-CoV-2 vaccine. The scale up of delivery programs for an interim vaccine such as BCG would still be a very useful infrastructural investment for more rapid roll-out of a subsequent definitive vaccine. There seems little to lose in terms of safety or opportunity cost, and potentially much to gain.
Based on previous experience and randomized controlled trials in adult and elderly individuals, the risks of VPM1002 vaccination are considered low. The objective of these trials is to evaluate the beneficial effects of VPM1002 vaccination through a lower work absenteeism rate of HCP and/or a mitigated clinical course of SARS-CoV-2 disease and other infectious diseases in HCP and the elderly.
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