Streptococcus pyogenes (GAS) is a pathogenic bacteria. It causes various suppurative diseases (like pharyngitis, impetigo, etc) and invasive diseases (like necrotizing fasciitis, toxic shock syndrome etc). There is heavy burden of GAS diseases in tropical region worldwide. It causes 616 million of pharyngitis and 1.78 million of severe disease each year. A 2013 survey stated that developing countries are suffering more severely than developed countries. Our strategy is to develop a universal vaccine against GAS using reverse vaccinology approach. First by combining Bioinformatics, Proteomics and Microarray data, we have identified 52 potential vaccine candidates which are either surface or secretory proteins. These 52 vaccine candidates expression was checked using qRT-PCR for both prevalent Indian serotypes (M1 and M49). Invasion assay along with qRT-PCR data revealed that M49 is more invasive as compare to M1. M49 is further used for in vitro Neutralization assay on HEp2 cells. Forty five sera were raised in mice against each recombinant protein candidate. Out of 45 sera candidates, 18 showed inhibition in adherence (>75%). FACS was used to determine whether the candidate is exposed on bacterial surface or not. Out of 18 sera, 10 protein candidates corresponding to sera were showing significant surface exposure in FACS. Four candidates selected by in vivo study are cloned, expressed and purified. Purified protein protection was checked in mice by in vivo survival assay using both Indian and Israel GAS. Functional immunization assays was used to determine immune response developed in mice immunized by vaccine candidates.