A potent vaccine against tuberculosis is getting readied at the Pune-based Serum Institute of India Limited. The institute started a ‘Phase 2b’ clinical trial in neonates in South Africa late last year using a novel, recombinant BCG (bacillus Calmette-Guérin) vaccine. The new TB vaccine (VPM1002) is based on the BCG vaccine in use today, but what makes it more powerful is that it contains a gene which makes it easier for the vaccine to be better recognised by cells of the immune system.
The ‘Phase 2b’ trial will be studying 416 babies (newborns) whose mothers are HIV-positive and negative. A single dose will be administered to babies immediately after birth and will be followed up for a year. The trial, to be completed by mid-2017, will study safety and the level of cellular immune response (which does not involve antibodies) produced by the vaccine.
A ‘Phase III’ trial involving newborns will begin in India once ‘Phase 2b’ ends. By the end of this year, the institute also plans an independent ‘Phase III’ trial, again in India, involving nearly 2,500 adult TB patients who have been successfully treated.
The rationale for targeting this high-risk subset of the adult population is because each year in India, TB recurrence (reinfection and relapse) is seen in at least 2,00,000-2,50,000 people who have been successfully treated. According to the medical director at the institute, Dr. Prasad S. Kulkarni, it will be easy to clinically prove the vaccine’s efficacy as the study will be restricted to a relatively fewer number of people.
The recombinant vaccine, which was developed by a group headed by the founding director of the Max Planck Institute for Infection Biology, Berlin, Stefan H.E. Kaufmann, has already shown promise in animal and small-scale human trials. Prof. Kaufmann said the amount of bacteria reduced 100-fold in all animals studied when the recombinant vaccine was administered. Studies in two separate ‘Phase I’ human clinical trials in 80 adults in Germany (2009) and 50 adults in South Africa (2010) and one ‘Phase 2a’ trial in 50 newborn infants in South Africa in 2012 have confirmed safety and sufficient strengthening of the immune system against TB, thus raising hopes for a higher efficacy vaccine.
The trials in Germany and South Africa were carried out by Vakzine Projekt Management GmbH (VPM), Hanover, Germany. The Max Planck Institute holds the patent and has licensed the vaccine to VPM; VPM, in turn, has out licensed it to the Serum Institute.
The recombinant BCG vaccine is intended to protect children and possibly adults against drug-sensitive and drug-resistant TB. The hope is that the vaccine will be able to protect against pulmonary and extra-pulmonary TB. In comparison, the classical BCG vaccine can only protect against severe forms of the disease in children but cannot prevent pulmonary TB in all age groups, including children.
More efficacious, safer Besides better efficacy, the recombinant BCG vaccine has been found to be superior safety-wise. Unlike the currently used vaccine that causes BCG-related disease in HIV-positive babies (as they have reduced immunity), the recombinant vaccine is expected to be safe in this population. Better safety of the new vaccine was demonstrated even during animal trials — immuno-compromised mice died when the existing BCG vaccine was administered but not when the recombinant vaccine was used. Prof. Kaufmann and others strongly believe that a difficult pathogen like Mycobacterium tuberculosis, which expresses some 3,000 different antigens, cannot be dealt with by a vaccine containing one or a few antigens. “Since BCG shares almost all antigens with tuberculosis, we decided to improve BCG with respect to its ability to provoke an immune response,” he said. “Indeed, our strategy has been termed by others as [a] rational vaccine design”.
The hypothesis was that the vaccine would induce broader cellular immunity (that does not involve antibodies) but something unexpected happened. “Antibody response was also seen in animals. This was unexpected and is good,” he said.
“The vaccine being tested is intended to replace the current BCG vaccine and will be administered to young children to protect them against tuberculosis. Adults may also be able to benefit from it later,” Prof. Kaufmann added.
Since its use in 1921, BCG has become the “most widely administered vaccine in history with approximately 4 billion doses administered worldwide”.
“Besides assured supply, [the] Serum [Institute] manufacturing the vaccine will mean that [the] cost will be reasonable,” said the Director-General of the Indian Council for Medical Research, New Delhi, Dr. Soumya Swaminathan.
With a capacity of 100 million doses, the Pune institute meets the global demand for BCG vaccine and is well equipped to supply the new vaccine when the trials are completed. This will mark the end of a long journey that began when the recombinant vaccine was constructed in the late 1990s and tested in different animal models to determine its safety and protective effect.