We recently developed self-destructing Salmonella strains that have superior attributes to display at high levels microbe associated molecular patterns (MAMPs) naturally or after cell damage to efficiently induce innate immunity effectors to augment the ability of subunit and live vaccines to induce protective immunity against challenges with pathogens. We recently determined that administration of some of these Self-Destructing Attenuated Adjuvant Salmonella (SDAAS) strains in ovo to 18-day old chick embryos permitted normal levels of hatchability. We therefore propose: (1) to optimize SDAAS strains to stimulate production of a sustained innate immunity and be safely used for in ovo inoculation of embryonated eggs without reduction in hatchability or in weight gain and feed conversion efficiency of the hatched chicks and (2) determine whether such in ovo SDAAS strain administration (in comparison to administering buffered saline) can reduce infection and colonization of day-of-hatch chicks by Salmonella, APEC/ExPEC, Campylobacter jejuni, Listeria monocytogenes and Clostridium perfringens. Objective (3) is to establish the basis for the observed results. Success in these endeavors will ensure the better health of chickens to enable better growth performance, enhance the safety of poultry for human consumption and reduce the use of antimicrobial drugs during poultry rearing and thus reduce the selective pressure for expansion in drug-resistant bacterial pathogens.