The Specific Aims of the proposal will be modified to reflect a change in scope, according to recommendations from the review panel. Specifically, the revised scope of the project will now only include AIM I and AIM II of the proposal. There will be no change in scope to the first two aims. All experiments proposed in AIMs I and II can be accelerated to meet the two year time commitment. Regarding AIM III:
the Aim III to investigate the systemic effects of the recombinant human lactoferrin using pre-IND, repeat dose toxicology protocols in two species (rat and dog) will be eliminated from the study. This is in line with the recommendation from the review panel that indicated toxicity studies are premature at this point of experimentation. """"""""COMMITTEE BUDGET RECOMMENDATIONS: The toxicity studies are deemed premature and recommended to be removed. The corresponding budget should be cut."""""""" Abstract (Modified):
The aims of this Phase II continuation proposal are to utilize fully humanized recombinant lactoferrin (rhLF) as an adjuvant to enhance the BCG vaccine to strengthen host defense against subsequent mycobacterial infection, and to limit pathogen induced tissue damage. The World Health Organization (WHO) estimates that roughly one third of the world's population is currently infected with MTB, and the incidence rate for new infections is approximately 0.6% per year. The BCG vaccine is variably effective against childhood tuberculosis disease manifestations, however, the response wanes in adulthood, potentially leading to disease development upon reinfection. The ability of lactoferrin to enhance the generation of antigen specific DTH responses suggests that lactoferrin could promote development of specific T-cell responses against a complex antigen, such as BCG. Therefore, we will capitalize on successful developments of Phase II studies to further the utility of rhLF for use in human trials. Areas that require further investigation concern (i) optimization of the immunization schedule for use of the adjuvant;and (ii) whether the production protocol developed for the initial expression of rhLF glycoform is robust and scalable. The implications of these research developments are critically relevant to the development of lactoferrin based vaccine adjuvants, as well as therapeutics against immune related pathologies.
The Mycobacterium bovis bacillus Calmette Guerin (BCG), an attenuated strain of M. bovis, is the current vaccine for tuberculosis (TB), a disease caused by the intracellular pathogen Mycobacterium tuberculosis (MTB). BCG is the most widely used vaccine in the world and has remained relatively unchanged since 1921 despite variable effectiveness. Our research goals have focused towards utility of recombinant human lactoferrin as an adjuvant to enhance the BCG vaccine and strengthen host defense against subsequent mycobacterial infection. This continuation request is essential to bridge positive results obtained from the Phase II with a sufficient assurance of the quality of final material to engage in pre-IND development of human recombinant lactoferrin for use as a vaccine adjuvant to combat M. tuberculosis infection.
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