Studies on new tuberculosis vaccine candidates in animal models

Background: Tuberculosis (TB) is a major health problem in many countries, especially in low income countries. Globally, TB causes more than 2 million human deaths annually and 1/5 of all adult deaths in developing countries. WHO estimates that one third of the world's population i.e. 1.9 billion people, are infected with M. tuberculosis (Mtb). The most cost effective way to combat infectious diseases is the preventive vaccination. Most of the world's population is vaccinated with the only available TB vaccine, the Bacillus Calmette-Guérin (BCG) vaccine that was developed a century ago. Even though the BCG vaccine protects the young child against disseminated TB disease it has none or little protective effect against adult pulmonary TB (PTB). PTB is the major disease manifestation of TB in adults and it causes death at the most productive age, further adding to poverty in already impoverished countries. Hence, the development of a new more efficient TB vaccine(s) is the highest priority in TB research. Aims: The aim of this thesis was to evaluate protective efficacy of new TB vaccine candidates with the long term goal to improve the efficacy of primary BCG vaccination against adult PTB by boosting with new vaccine(s). Results: New vaccine candidates and adjuvant/delivery systems for mucosal applications were developed and tested in animal models. Lipoarabinomannan (LAM) was purified from a virulent Mtb strain and used to prepare novel oligosaccharide-protein conjugate vaccines. To avoid the immuno-suppressive effects of the intact LAM molecule while taking advantage of its carbohydrate antigen epitopes, LAM was de-lipidated and split into oligosaccharides by partial chemical degradation. The arabinomannan oligosaccharides (AM) were used to prepare AM-protein conjugate (AM-Prot) vaccines and to generate a large number of monoclonal antibodies (MoAbs). Adjuvants can augment the immune response to many vaccine antigens and for some sub-cellular vaccines e.g. Diphteria and Tetanus vaccine, they are essential. There is a vast number of experimental adjuvants but most of them are intrinsically toxic and only few can be considered for use in man. Aluminum salts are so far the only adjuvants approved for large scale human use. In this thesis a new adjuvant L3 was investigated. L3 is non-toxic and approved by the Swedish FDA for human phase I/II trials. The different AM-Prot vaccines and a vaccine based on heat killed whole-cell BCG (H-kBCG) were formulated with L3