Fiber optic label-free biosensors are currently experiencing wide diffusion, as they combine the performance of optical measurements with the advantages of optical fiber. This paper presents a comprehensive review about the design, development and testing of biosensor solutions based on in-fiber long period gratings (LPG). The attention is focused on optical transducers and methodologies allowing a significant enhancement of the sensitivity. Moreover, we report here about the development of a novel fiber optic biosensor based on unconventional LPG. The sensing platform is based on a long period grating (LPG) inscribed into a specialty double cladding fiber, whose sensitivity is enhanced through the mode transition phenomenon by chemical etching of the fiber outer cladding. The LPG is further covered with a nanosized layer of graphene oxide, providing carboxylic functional groups for the covalent immobilization of a vitamin D specific antibody. The testing was conducted using the major circulating form of vitamin D3, i.e., 25-OH- D3 (molecular weight ~400 Da), for which concentrations within 10-1000 ng/mL in buffer solution were measured.