In 1993, the World Health Organization (WHO) declared tuberculosis (TB) a global emergency. Approx. 1.7 billion people are infected and 10 million people are estimated to have fallen ill with TB in 2018. In the same year, approx. 1.5 million died because of TB; among them 205,000 children (aged 0-14 years). South Africa and other Sub-Saharan countries belong to the group of "high-burden" TB countries with an estimated total incidence of 301,000 TB cases in 2018 in South Africa alone. In children BCG can protect against, or at least ameliorate, severe forms of systemic TB, particularly TB meningitis. To interrupt transmission of disease, highly contagious pulmonary forms of TB need to also be targeted by vaccination. Unfortunately, BCG fails to achieve this. Additionally, the current BCG shortage endangers global child health and further highlights the need for a novel TB vaccine.
Bacillus Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis (M. bovis), is the only TB vaccine available since 1921 and the oldest vaccine currently used. Although BCG protects against disseminated TB (TB meningitis and miliary disease) in young children, it offers limited protection against either childhood pulmonary TB (>75 % of the paediatric disease burden) or adult TB. Nevertheless, BCG remains the standard of care for primary TB prevention for infants in most developing countries.
Sizeable BCG shortages are a life-threatening problem since 2013. Therefore, there is an urgent need to develop a BCG replacement which is not only more effective, but also can be produced in a way that meets the global demands in a reliable manner.
A phase II clinical trial in the target population of HIV-exposed and HIV-unexposed infants has recently completed the follow-up in South Africa (416 newborn infants recruited) and is investigating safety and immunogenicity of VPM1002 in these infants.
The proposed pivotal phase III trial is funded by Serum Institute of India (SIIPL) and is part of the EDCTP2 programme supported by the European Union. Approximately 7,000 healthy male and female newborn infants in South Africa, Tanzania, Kenya, Uganda and Gabon are planned to be recruited. The study cohort will consist of HIV-unexposed as well as HIV-exposed newborn infants vaccinated with either BCG SII or VPM1002 to evaluate efficacy and safety, also in immune-compromised populations.
After successfully conducting this pivotal phase III trial, the development of VPM1002 aims to apply for marketing authorization in order to make this novel vaccine available to newborn infants in Sub-Saharan countries and worldwide.
The vaccine VPM1002
VPM1002 (M. bovis BCGΔureC::hly) is an innovative live vaccine against TB, based on the well-known Mycobacterium bovis (M. bovis) Bacille Calmette-Guérin (BCG) strain which has been administered approximately 4 billion times worldwide. The genetically modifications of VPM1002, namely introduction of listeriolysin and simultaneous deletion of the gene for urease C in the BCG genome, are aiming for better recognition by the host immune system.
Listeriolysin, a gene of Listeria monocytogenes (L. monocytogenes) coding for the respective protein, perturbates the phagosome and allows release of vaccine-derived antigens into the cytosol. In the cytosol, these antigens are additionally accessible for the Major Histocompatibility Complex (MHC)-class-I pathway, whereas BCG antigens are kept in the phagosome and therefore are mainly directed towards the MHC-class-II pathway. Urease C catalyzes the hydrolysis of urea into carbon dioxide and ammonia, thus creating a basic environment. Its deletion was necessary as the aforementioned listeriolysin is optimally active under acidic conditions. Furthermore, VPM1002 induces apoptosis and autophagy, which allows cross-presentation of antigens and superior clearance of the vaccine
A gene of L. monocytogenes coding for the protein listeriolysin has been integrated into the genome of BCG. Listeriolysin is responsible for the formation of pores in the phagosome after endocytotic uptake of the bacterium, enabling antigens and DNA of the bacterium to translocate into the cytosol. Further, BCG's gene for urease C (ureC) has been inactivated in VPM1002. Urease C catalyzes the hydrolysis of urea into carbon dioxide and ammonia, thus creating a basic environment.
This principle was utilized in VPM1002. In contrast to BCG which is trapped inside the phagosome and, thus, is targeted towards the MHC-class-II pathway, VPM1002 forms pores into the phagosome via listeriolysin and translocates mycobacterial antigens into the cytosol, ultimately leading to MHC-class I presentation of bacterium-derived peptides. MHC-class-I presentation and subsequent induction of CD8+ T-cells resembles the natural mechanism of protection against the TB causing agent, Mycobacterium tuberculosis, more closely and, thus, is believed to be the appropriate means for improving the induction of immunity.
The vaccine is formulated as live lyophilised bacteria to be resuspended before intradermal injection.
The manufacturing process of VPM1002 is well established and can be scaled up to meet the worldwide demand.