Despite decades of research, Newcastle disease (ND) persists as a continual threat to the poultry industry. Current vaccines have not been able to markedly reduce the global prevalence of disease and cannot prevent replication and shedding of the challenge virus; therefore, improved vaccines are required. To evaluate the effect of genotype-specific ND vaccines, a chimeric virus expressing the F and HN genes from a genotype XIII vNDV (rLS-PK33) was developed. Specific-pathogen-free chickens were vaccinated with LaSota or rLS-PK33 live vaccines at different doses, and challenged with virulent PK33 to evaluate and compare their performance on preventing mortality and challenge virus shedding. In addition, a plasmid and an attenuated ND virus expressing chicken IFN- (rZJ1*L/IFN), and an attenuated NDV expressing chicken IL-10 (rZJ1*L/IL-10) were developed to investigate their effect on modulating the immune response in chickens and their effect on protection and reduction of virus shedding after challenge with vZJ1. Cloning and reverse genetic techniques were utilized for the development of all recombinant viruses. These were characterized by sequencing of the fusion protein cleavage site and inserted genes, intracerebral pathogenicity index assay, mean death time assay in eggs, ELISA and Western blotting for cytokine determination, virus isolation and titration in eggs, hemagglutination inhibition assay for antibody quantification, and lymphocyte proliferation assays and flow cytometric analysis for evaluation of cellular immune response. Our results reveled that rLS-PK33 decreased viral shedding more efficiently than LaSota; additionally, it was able to increase survival rates better than LaSota when administered at suboptimal doses. Evaluation of the effects of chIFN- delivered by plasmid DNA, live or inactivated rZJ1*L/IFN, demonstrated that, regardless of the delivery system, chIFN- did not enhance the immune response. On the contrary, evaluation of the effect of chIL-10 delivered by inactivated rZJ1*L/IL-10, resulted in an increased antibody response and lower antigen-specific T cell response, without increasing morbidity and mortality after challenge. In conclusion, these results provide new strategies to improve ND vaccines, and provide new insights to better understand the chicken immune response, as well as the effects of two key avian cytokines on immune response modulation.