Evaluation of the Mtb72F Polyprotein Vaccine in a Rabbit Model of Tuberculous Meningitis

Abstract

Using a rabbit model of tuberculous meningitis, we evaluated the protective efficacy of vaccination with the recombinant polyprotein Mtb72F, which is formulated in two alternative adjuvants, AS02A and AS01B, and compared this to vaccination with Mycobacterium bovis bacillus Calmette-Guérin (BCG) alone or as a BCG prime/Mtb72F-boost regimen. Vaccination with Mtb72F formulated in AS02A (Mtb72F؉AS02A) or Mtb72F formulated in AS01B (Mtb72F؉AS01B) was protective against central nervous system (CNS) challenge with Mycobacterium tuberculosis H37Rv to an extent comparable to that of vaccination with BCG. Similar accelerated clearances of bacilli from the cerebrospinal fluid, reduced leukocytosis, and less pathology of the brain and lungs were noted. Weight loss of infected rabbits was less extensive for Mtb72F؉AS02A-vaccinated rabbits. In addition, protection against M. tuberculosis H37Rv CNS infection afforded by BCG/Mtb72F in a prime-boost strategy was similar to that by BCG alone. Interestingly, Mtb72F؉AS01B induced better protection against leukocytosis and weight loss, suggesting that the polyprotein in this adjuvant may boost immunity without exacerbating inflammation in previously BCG-vaccinated individuals.The development of improved tuberculosis (TB) vaccines has been recognized as a major public health priority by the World Health Organization. At present, the attenuated strain of Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only vaccine that is widely used against TB (7, 17). The BCG vaccine is relatively effective against the progression of infection to disseminated TB and tuberculous meningitis (TBM) in children (38). It has limited efficacy, however, against pulmonary TB in adults (16,35,48). An improved vaccine that protects both children against TBM and adults against pulmonary TB disease would be very useful in combating TB. Consequently, a number of research groups are engaged in developing more effective anti-TB vaccines by utilizing either new attenuated live vaccines (4,12,20,22,39,40,47,49) or subunit protein vaccines (3,6,11,26,34,37,41). While attenuated live vaccines provide prolonged exposure of the host immune system to newly synthesized antigens, the advantage of subunit vaccines is the possibility that their efficacy may not be compromised by exposure to environmental mycobacteria (5) or by prior BCG vaccination (8).To adequately predict the efficacy of any new anti-TB vaccine in humans, it is imperative to develop assays for measuring the level of protection that the vaccines provide. Animal models of infection are useful tools for this purpose. In our previous studies, we established and characterized a rabbit model of TBM which mirrors human central nervous system (CNS) disease (45). In this model, mycobacteria are inoculated directly into the cisterna magna of rabbits and the course of infection and the host response are monitored. We are using this animal model of CNS infection to evaluate the efficacy of new candidate vaccines for protecting the host against both infection...

Defined tuberculosis vaccine, Mtb72F/AS02A, evidence of protection in cynomolgus monkeys

“…In this regard, a strategy of repeat immunizations with BCG has not increased protection in either animals or humans (10,11), perhaps because preexisting immunity prevents the booster dose from persisting in the vaccinee. GSK, in collaboration with Corixa Corporation, has developed a defined subunit vaccine, Mtb72F/ AS02A, that is capable of boosting BCG and was shown to confer protection in 3 experimental models of TB, the mouse (3), guinea pig (3,6), and rabbit (12). In this report, we demonstrate that this vaccine candidate induces long-term protection against disease and death in the cynomolgus monkey model of TB.…”

Central Nervous System Tuberculosis: Pathogenesis and Clinical Aspects

“…That group went on to use this model to evaluate the efficacy of a recombinant polypeptide vaccine (225), demonstrate the importance of TNF-␣ for the progression of TBM (224), and evaluate the potential role of thalidomide and its analogues in the course of TBM (226,227).…”

Evaluation of the Safety and Immunogenicity of Two Antigen Concentrations of the Mtb72F/AS02ACandidate Tuberculosis Vaccine in Purified Protein Derivative-Negative Adults

“…Mtb72F, formulated with GSK Biologicals' proprietary AS02 A adjuvant system, was shown to be well tolerated in animal models and protected against M. tuberculosis challenge in nonhuman primates, where Mtb72F/ AS02 A was shown to be capable of inducing long-term protection against tuberculosis, as determined by protection against severe disease and death and by other clinical and histopathological parameters (6,30,34,39). A first-time-in-human study evaluated Mtb72F/AS02 A (10 g) in purified protein derivative (PPD)-negative TB-naïve, healthy adults in the United States given according to a 0-, 1-, and 2-month schedule and was found to be clinically well tolerated and highly immunogenic (42).…”